The association between XRCC1 Arg194Trp polymorphism and glioma risk were inconsistent from published meta-analyses and epidemiological studies. Hence, we performed this updated and cumulative meta-analysis to reappraisal this relationship. PubMed, Embase, CBM , and CNKI  databases were comprehensively searched up to August 13, 2016 . After study selection and data extraction from eligible studies, the association was evaluated by odds ratios (ORs) and its 95% confidence intervals (95%CIs) using Comprehensive Meta-Analysis software. Finally 16 case-control studies involving 7011 patients and 9519 healthy controls were yielded. The results indicated that XRCC1 Arg194Trp polymorphism was significantly correlated with the increased risk of glioma . Cumulative analysis showed the results changed from non-significant to significant when new studies accumulated, and sensitivity analysis indicated the results were stable. Subgroup analysis showed the significant association existed in Asians but not in Caucasians. Current evidence indicated that XRCC1 Arg194Trp polymorphism was associated with increased risk for glioma, especially in Asians; however, relevant studies involving other ethnic groups are required to validate our findings in further. Glioma is the most common and the worst prognosis on primary central nervous system (CNS) tumors, making up approximately 30 % of all brain and CNS tumors and 80 % of all malignant brain tumors , 2. HoweFrom 2012 to 2016, there are 14 meta-analyses –20 publiThe primary search yielded 208 potentially related publications and finally 16 case-control studies involving 7011 patients and 9519 healthy controls were included –39. FiguI2= 73.96%; for TrpTrp vs. ArgArg: OR = 1.66(1.31-2.12), I2 = 45.84%, Figure I2 = 91.01%; for TrpTrp vs. ArgArg+ArgTrp: OR = 1.47(1.26-1.72), I2 = 13.64%; TrpTrp+ArgTrp vs. ArgArg: OR = 1.17(1.01-1.35), I2 = 72.60%, respectively].Table The cumulative meta-analysis accumulated the studies according to the publication year which displayed that the association change from non-significant to significant with new studies accumulated, and the CIs became increasing narrower Figure . SensitiIn the subgroup analysis for ethnicity, no significant association was found in Caucasians under all five genetic models, but significantly increased risk was observed in Asians under for contrasts . After stratified analysis by source of controls, significant results were found both in hospital -based  and significant results for population-based controls (TrpTrp vs. ArgArg). Significant association existed in the studies conforming to HWE under two genetic models (TrpTrp vs. ArgArg and TrpTrp vs. ArgArg+ArgTrp) and in the studies deviating from HWE under all five genetic models.As shown in Figure The first study on the association between XRCC1 Arg194Trp polymorphism and glioma risk was performed by Liu et al in 2007 , involviObviously, their results are inconsistent . NowadayThe results of our meta-analysis are opposed to the conclusions from previously six meta-analyses in overall population , 15, 16,Our meta-analysis also is similar with the previous eight meta-analyses , 17–20. Our meta-analysis also has its limitations. First, the primary studies only provided data regarding Caucasians and Asians; therefore, more studies involving other ethnicities such as African should be conducted to validate our results. Besides, the important information such as histological types should be improved in further studies. Second, other factors that might contribute to the heterogeneity, such as age, histological types, gender could not be explored due to the lack of relevant data were in original studies. Third, for lacking recommended quality assessment tool , it was In conclusion, the results of the present meta-analysis suggest that the XRCC1 Arg194Trp polymorphism is associated with increased risk of glioma, especially for Asians. Of course, the results of our meta-analysis should be treated with caution, but unlike previous meta-analyses, we do not need to emphasize that relevant studies should be carried out for enlarging the sample sizes.This meta-analysis was reported following the recommended Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .The study was included according to the following criteria: (1) the study assessed the association between the glioma and XRCC1 Arg194Trp polymorphism; (2) the study reported ORs and 95%CIs, or the number of individual genotypes in both case and control groups for their calculation; (3) the design was case-control or cohort study; and (4) the patients were microscopically diagnosed as glioma. In addition, if studies had the overlapping data, only the largest or the most complete one was included in the final analysis.The PubMed, Embase, CBM , and CNKI  databases were comprehensively searched up to August 13, 2016  using the following terms: (polymorphism OR mutation OR variant) AND  AND (XRCC1 OR “x-ray cross complementing group 1”). Additional studies were manually searched from the references of all identified studies and the recent reviews.Two authors selected studies according to the criteria listed above and extracted information from all eligible studies independently. The essential information contained the first author’s name, year of publication, country of origin, ethnicity of subjects, source of control, genotyping method, number of cases and controls and genotype frequency, ORs and its 95%CIs, and HWE for controls. All disagreements were resolved by consulting with a third author.I2 statistics [I2 ≤ 40% was considered no substantive heterogeneity existed, so the fixed effect model was employed; otherwise, the random-effects model was used [p values were two-sided.First, the heterogeneity among included studies was detected using atistics . The valwas used . The OR was used –53: allewas used , 23. Thewas used . All thewas used , 52, 53


Glycaemic alterations are prevalent and modifiable secondary insults with detrimental consequences in neurocritically ill patients. Without discerning whether hyperglycaemia is a marker of lesional severity or the cause of brain damage, its association with poor results is clear due to its deleterious effects by promoting inflammation, thrombosis of the microcirculation and immunosuppression, among others. On the other hand, both the duration and depth of an episode of hypoglycaemia have a negative influence on final outcome. Despite this, a general consensus regarding the best glycaemic control in traumatic brain injury (TBI) has not been established yet.We read with great interest the article “Glycaemic control targets after traumatic brain injury: a systematic review and meta-analysis” by Hermanides et al. . AlthougP = 0.57). By removing the study by Bilotta et al., the risk of moderate hypoglycaemia is higher with intensive glycaemic control . This is relevant because intensive glycaemic control has been associated with moderate and severe hypoglycaemia, which have been associated with poor outcomes.Second, after analyzing the data from the included studies and performing a sensitivity analysis using the leave-one-out method in Stata v.13, we found that a single study  was infP = 0.39)  Fig. .Fig. 1FoFinally, we have two simple questions. Microdialysis studies have revealed that lowering levels of glycaemia below 110 mg/dL is associated with the development of metabolic crises in a brain vulnerable to glucose deficit; therefore, should the definitions of hypoglycaemia not be reconsidered in this context? And is the dichotomized Glasgow Outcome Scale a good form to evaluate the final outcome in severe TBI? We thank Rafael Núñez-Patiño and coworkers for their interest and comments on our article , to whic2 > 95%), with the influence of the Bilotta study clearly shown in the forest plot . We cho in . We ig. 6 in .Second, we thank Núñez-Patiño for performing a meta-analysis on length of stay for the different studies. We did not include this as an endpoint in our paper because ICU length of stay is not a patient-centred outcome and can be manipulated by many factors, including competing risk of death. The interpretation thus warrants caution.Finally, we agree with Núñez-Patiño et al. that microdialysis glucose levels may be important, but we need to recognize that they do not address the risks of hyperglycaemia either cerebrally or extracranially. We have to be aware that ICU research is littered with interventions that made the numbers better but the patients worse.To conclude, we agree that any meta-analysis should be interpreted with caution, especially in cases of marked heterogeneity. However, excluding studies from meta-analysis should be done based on predefined inclusion and exclusion criteria, and not because we do not ‘like’ the results.


I2 = 79.6%, p < 0.05. The dose–response analysis showed that every 10 g/d increment in alcohol consumption was associated with 7% increased gastric cancer risk . This meta-analysis provides evidence that alcohol consumption is an important risk factor of the incidence of gastric cancer.We performed this meta-analysis to explore the precise quantification relationship between alcohol consumption and gastric cancer and to provide evidence for preventing gastric cancer. We searched PubMed, Embase, and Web of Science for articles published up to December 2016, and identified 23 cohort studies that included a total population of 5,886,792 subjects. We derived meta-analytic estimates using random-effects models, taking into account correlations between estimates. We also investigated the dose–response relationship between gastric cancer risk and alcohol consumption. We found that alcohol consumption increased gastric cancer risk, where the summary risk ratio was 1.17 : 1.00–1.34;  Although the death rate of gastric cancer has declined for several decades, epidemiological data from the American Association of Cancer suggest that gastric cancer is the fourth and fifth most common cancer in men and women, respectively, and it remains a major public health problem worldwide , 2. As tHelicobacter pylori infection, dietary factors, smoking, family history of cancer), multi-stage developmental process; the exact cause of the disease is still not fully understood [The occurrence of gastric cancer involves a multi-factorial  with a heterogeneity value (I2) of 79.6% , 1.00–1.34; As the studies differed in terms of geographic area , sex , impact factor (> 3 or ≤ 3), and NOS score (6/7/8), we conducted subgroup analyses to determine the effect of these factors on our analyses Table . We obtap > 0.5).Dose–response analysis was performed using the available data Figure . Overallp > 0.05 and p > 0.05, respectively.The Egger and Begg regression models  revealedMeta-analysis is a method of summarizing the results of the same research purpose and comprehensively evaluating its combined effect. It can be objective, systematic, comprehensive, qualitative, and quantitative statistical analysis . ConsideN-nitroso compounds [H. pylori is another risk factor of gastric cancer [H. pylori is essential. However, only one study reported the RR for alcohol consumption and gastric cancer adjusted for H. pylori [The occurrence of gastric cancer is closely related not only to dietary factors, but also some non-dietary factors, which play an important role . We usedompounds , 38. In c cancer , 40; the. pylori .The limitations of the present meta-analysis should be noted. Only studies written in English were included; studies that were not written in English would have been overlooked. In our meta-analysis, there was heterogeneity across the studies, and regulation testing showed that geographical area was associated with ∼53.7% reduction in heterogeneity across the studies. We did not have information on wine variety classification; as wine varieties might differ between regions, the results would also have differed. Furthermore, heterogeneity among studies was allowed to account for the use of the random-effects model. Meta-analysis is an observational study, and bias in the design, data collection, and statistical analysis of a meta-analysis is unavoidable; accordingly, the quality of the data is used to evaluate and decide if here will be bias.Our meta-analysis had several strengths. To improve the statistical power, we included several studies, all of which were prospective cohort studies. This design minimizes selection and recall bias.p < 0.05 and an I2 value of 79.6%. Due to the limitations mentioned above, more high-quality cohort studies are required to strengthen the findings.In conclusion, our meta-analysis reveals a negative association between alcohol consumption and gastric cancer risk, with an RR value of 1.17 , Embase (http://www.embase.com/), Web of Science (http://wokinfo.com/), and Cochrane Library (http://www.thecochranelibrary.com/) databases to identify articles using the terms “alcohol beverages/consumption/drinking” and “gastric/stomach cancer/neoplasms/tumor/malignancy”. In addition, we reviewed the reference lists of the 23 included studies to identify additional studies. The language of the studies was limited to English, and we did not search for unpublished studies. In addition to the reference lists of the included studies, we also searched those listed in the Meta-analysis Of Observational Studies in Epidemiology guidelines [We updated the systematic literature review published in 2012 . We usedidelines , 42. We idelines .We included prospective cohorts of alcohol consumption and gastric cancer incidence. The inclusion criteria were: (1) a prospective cohort design; (2) investigation of the association between alcohol consumption and gastric cancer incidence; (3) reported the OR or RR with 95% CI; and (4) prospective cohort studies. For the dose–response analysis, a quantitative measure of intake had to be provided. When there were several publications from the same study, we selected the publication with the largest number of cases and the longest study period.Q and I2 statistics to estimate heterogeneity among the studies; disagreements were resolved by discussion. Two authors assessed the methodological quality of the included studies independently using the NOS.From each study, we extracted the first author’s last name, year of publication, country in which the study was conducted, age, duration, number of cases, exposure range, adjusted OR, RR, or hazard ratio (HR) with the 95% CI and adjustments, NOS score, and impact factor . The RR Q (p ≤ 0.10) and I2 statistics to examine heterogeneity across the studies and used the random-effects model when substantial heterogeneity was detected [The association between alcohol consumption and gastric cancer risk was assessed using the RR. We used detected . Subgroup < 0.05 was considered statistically significant. We used Egger’s linear regression and Begg’s rank correlation to evaluate potential publication bias.Data analyses were performed with STATA version 13.0;


Metformin and insulin differently affect the risk of colon cancer in type 2 diabetic patients, however their effects on colon adenoma is not clear. PubMed, ISI, Scopus and Cochrane databases were searched for studies reporting. The outcomes were total adenoma; advanced adenoma and recurrent adenoma. Traditional and Bayesian meta-analysis were conducted via random-effects models. Odds ratios (OR) with 95 % confidence intervals (CIs) / or credible intervals (CrI) were used to describe the ratio of different events. A random-effects model described by DerSimonian and Laird was performed, when significant between-study heterogeneity existed. Alternatively, an inverse variance fixed effects model was used, when there was no significant heterogeneity across studies. The potential publication bias was assessed with funnel plot, Egger and Begg's regression asymmetry tests. Moreover, “trim and fill” procedure was used to assess the possible effect of publication bias. For metformin intake, 11 studies (51991 patients) were included. The results showed that metformin significantly decreased the risk of advance adenoma . The risk of total adenoma was not associated with metformin use , and metformin did not affect the risk of adenoma recurrence . Five studies (2678 patients) were included in the analysis to determine the effect of insulin therapy. Insulin significantly increased the risk of colorectal adenoma . These findings indicate that metformin has no protective effect on total and recurrent adenoma, whilst it significantly reduces the risk of advanced adenoma, but insulin increases the risk of total adenoma.  CRC: Colorectal cancerT2DM: Type 2 diabetes mellitusAMPK: AMP-activated protein kinaseCI: Confidence intervalCrI: Credibility intervalOR: Odds ratioMCMC: Markov chain Monte CarloColorectal cancer (CRC) is one of the most common cancer globally, it has been shown that the incidence of CRC has been increasing worldwide . ColoreMetformin is another potent anti-hyperglycemic drug. It can decrease hyperinsulinemia, increase insulin sensitivity  and redSome animal studies have revealed that metformin prevents the proliferation of colonic epithelial cells . A few A systematic search of the online databases PubMed, ISI, Scopus, and Cochrane Collaboration up to January 2017 without any restrictions was conducted to find published articles. Search terms were: (“Metformin”) OR (“Insulin”) AND  AND . All eligible studies were reviewed, and their bibliographies were checked for other relevant publications. For carrying out and reporting meta-analyses of observational studies, the standard criteria were followed. Agreement on the selection of studies between the two reviewers was evaluated by the kappa coefficient. Meta-analysis was performed using both traditional and Bayesian meta-analysis. When the two methods produced different results, the results of Bayesian method was approved. The effect sizes were calculated based on total colorectal adenoma, advanced adenoma, and recurrence of adenoma in diabetic metformin users and also for the total colorectal adenomain diabetic insulin users compared with controls. Briefly, the odds ratio  / or credible intervals (CrI)) were used to describe the ratio of different events occurring in diabetic patients. An Inverse Variance fixed effects model was used to calculate the pooled effect measure. Otherwise, the random effects model described by DerSimonian and Laird (1986) was app2 statistic and Cochrane's Q-statistic .In the presence of significant statistical heterogeneity, apart from the random-effects model, sensitivity analyses were performed to evaluate the consistency of our results. Firstly, to evaluate any possible excessive influence of a single study, we examined whether the exclusion of this study substantially altered the magnitude or heterogeneity of the summary estimate. This was achieved by repeating the meta-analyses with exclusion of each individual study one at a time, to assess the overall effect of the exclusion on the pooled Ors .SecondlIn Bayesian hierarchical random-effects models , as a vague prior, is placed upon the pooled effect size. As our meta-analysis include small numbers of studies, there was little information in the likelihood regarding the estimation of the between study variance parameter. In this situation. The prior can be influential in the analysis . In thiThe likelihood of publication bias was assessed by constructing funnel plots (not shown), which were obtained by plotting the log ORs vs. SE of individual studies. Their symmetry was estimated by Egger's regression test and the Begg and Mazumdar adjusted rank correlation test . Therefore, the effect size was pooled using the random-effects model. The metformin use was not significantly associated with reduced incidence of total adenoma among T2DM patients .The results of Bayesian hierarchical modeling were generally similar to those obtained using the traditional meta-analysis. The Bayesian credible intervals (CrI) were reasonably wider than the traditional confidence intervals (CI), , as they accounted for additional variability. Also the risk of recurrence adenoma was not significantly lower among metformin users than controls (non-metformin users) pooled ORs (95 % CI) was 0.89 (0.76-1.04). Furthermore, the heterogeneity between 4 studies based on recurrent adenoma outcome was not significant  then, the effect size was pooled using the fixed-effects model. . The result of both traditional and Bayesian approaches is shown in Table 3The small number of studies on advanced adenoma leads to Bayesian meta-analysis. The significantly reduced advanced adenoma polyps was found in diabetes treated with metformin use  prior for mean OR and Gamma distribution for between study variance are presented in Table 3For the Bayesian hierarchical modeling, we used several different prior distributions for parameters. The results showed that changing the form of supposed prior distribution had a minimal effect on pooled estimation. The results using N , and adenoma recurrence (P=0.152). For total adenoma, in order to quantify the amount of bias in the publication (P =0.048) the modification of the final meta-analysis results according to “trim and fill” method did not differ from the results of the Classic meta-analysis (summary estimate of OR (95 % CI)).The summary ORs of meta-analysis  revealed that there was a significant positive association between colorectal adenoma incidence and insulin intake between T2DM patients according to the 5 including studies  in related meta-analysis. Therefore, the effect size pooled using the fixed-effects model. The results of Bayesian hierarchical modeling was inconsistent with the result of the traditional meta-analysis  (Table 3The significant heterogeneity was not identified (I) Table 3. Also thWe conducted the subgroup analysis based on the study location, age of the patients and the study design Table 4. The resThis may be for the age as a risk factor of colon polyps, especially in diabetic patients. The results of subgroup analyses based on the study design showed that there was no difference between cohort and case-control study design.This meta-analysis sought to identify whether T2DM with and without metformin intake history have different risk in order to colorectal adenoma, using both conventional and Bayesian meta-analyses. Compared to traditional meta-analyses, we used also the Bayesian approach that takes into account all sources of variation and reflects these variations in the pooled result. The main results of this meta-analysis of 11 observational studies on the metformin use and risk of colorectal adenoma were three fold. First, analysis propose that metformin intake will significantly decrease the risk of advanced adenoma (OR= 0.51). Second, the risk of total adenoma is not associated with metformin use between type 2 diabetes (OR= 0.86) and third, results for the pooled ORs indicate that, there was no statistical association between metformin intake in diabetic patients and adenoma recurrence (OR= 0.89).In the subgroup analyses, after stratifying studies by location, we showed that metformin therapy was associated with a significant reduction in colorectal adenoma risk in Asian population, while no significant association was found in North Americans. This can be explained by dietary habits and/or other cultural and behavioural differences. For example, red meat and milk products, as well-known colorectal adenoma risks, are more popular in western countries . AnotheWe also provided some evidence that metformin may not have beneficial effects against recurrence colorectal adenoma. The present study is an analysis based on the epidemiological studies which included large-scale and long-term follow-up results. Insulin significantly increases the risk of colorectal adenoma in T2DM patients (OR:1.43), however in this analysis due to lack of data we could not report data on stratified analysis by duration of insulin use duration of DM or age.In conclusion, our meta-analysis indicates that metformin is associated with a reduction in risk of colorectal adenoma incidence in individuals with T2DM, compared with insulin treatment which significantly increases the risk of colon adenoma. So similar to CRC, DM medication may affect the risk of CRA.The authors would like to thank Dr. Erfan Sadeghi for his kindness. For this type of study, formal consent is not required.The authors declare that they have no conflict of interest.Master of sciences thesis in number of 395963.


The aim of this study was to conduct a meta-analysis on studies exploring this association. Data from nine studies were eligible, of which five were case-control and four were cohort studies. Results from meta-analysis showed a positive association between increasing DII scores, indicating a pro-inflammatory diet, and CRC. Individuals in the highest versus the lowest (reference) DII category showed an overall 40% increased risk of CRC with moderate evidence of heterogeneity . When analyzed as a continuous variable, results showed an increased risk of CRC of 7% for a 1-point increase in the DII score. Results remained unchanged when analyses were restricted to the four prospective studies. Results of our meta-analysis support the importance of adopting a healthier anti-inflammatory diet in preventing CRC. These results further substantiate the utility of DII as tool to characterize the inflammatory potential of diet and to predict CRC.Diet and chronic inflammation of the colon have been suggested to be risk factors in the development of colorectal cancer (CRC). The possible link between inflammatory potential of diet, measured through the Dietary Inflammatory Index (DII Colorectal cancer (CRC) is the third most common form of cancer worldwide and is one of the leading causes of cancer-related deaths . Inciden®) was based on literature published on diet and inflammation through 2010   AND (cancer OR carcinoma OR neoplasm)}. Reference lists of retrieved articles were manually searched by two researchers (G.G. and S.N.). The literature search was limited to English. If more than one article was published using the same cohort, the most recent article with the longest follow-up period was considered. Studies included in this systematic review met all of the following inclusion criteria: (i) focused on humans and had a case-control or a prospective study design; and (ii) evaluated the risk or association between the DII and CRC. The two investigators independently assessed articles for compliance with the inclusion and exclusion criteria and resolved disagreements through consensus.The following information was extracted from each study: (i) name of the first author; (ii) year of publication; (iii) study cohort or name; (iv) country; (v) number of participants; (vi) sex of participants; (vii) age range or mean age of the study population at baseline; (viii) follow-up period; (ix) endpoints and cases; (x) measures of risk [hazard ratios (HRs)] or association [odds ratios (ORs)] with 95% confidence intervals (CIs) for the highest versus the lowest category of exposure and for 1-point increase of the DII score (when available); and (xi) covariates used for adjustment.The quality of observational studies was assessed according to the Newcastle-Ottawa Quality Assessment Scale , consistI2 statistic. The significance of the Q test was defined as p < 0.10. The 2I statistic represents the amount of total variation that could be attributed to heterogeneity. 2I values ≤25%, ≤50%, ≤75% and >75% indicated no, little, moderate, and high heterogeneity, respectively. A sensitivity analysis was conducted by excluding one study at a time in order to assess the stability of results. Subgroup analyses were conducted by tumor localization , sex, geographical region , and adjustment for smoking, BMI, physical activity and non-steroidal anti-inflammatory drug (NSAID) use. Publication bias was assessed by visual observation of funnel plots. All analyses were performed with Review Manager (RevMan) version 5.2 .In this meta-analysis, ORs and HRs were deemed equivalent to relative risks (RRs) . Random-The relevance of studies was assessed with a hierarchical approach on the basis of title, abstract, and the full manuscript. The full process of identification and selection of studies is shown in The nine studies selected included a total of 881,612 individuals and 18,888 cases of colorectal cancer available for the present meta-analysis.I2 = 69%, p < 0.001; I2 = 50%, p = 0.08; I2 = 69%, p < 0.001), and in separate analysis for prospective cohorts  and case-control studies . Subgroup analyses showed no differences between any of the groups investigated  DII category of exposure had an overall 40% increased risk of colorectal cancer with moderate evidence of heterogeneity  DII category of exposure, with similar characteristics reported for the general analysis .Results from this meta-analysis of nine studies that have examined the association between inflammatory potential of diet, as measured by the DII, and CRC, showed strong evidence of positive association between the DII and CRC. This persisted across tumor location. Therefore, limiting consumption of pro-inflammatory foods, such as red meat, and increasing consumption of anti-inflammatory components, like fruits and vegetables, may play an important role in reducing the risk of CRC. The DII score is calculated from several components and important among them are polyphenols such as flavonoids. Isoflavones, flavanol, flavan-3-ol, anthocyanidins, flavones and flavanones which form the six major groups of flavonoids are included in the DII calculation and all of these are anti-inflammatory and therefore have negative inflammatory effect scores .r = −0.65, p < 0.01), AHEI , and the DASH  [r = −0.45, p < 0.01) [The DII is a literature-derived population-based dietary index developed specifically to measure the inflammatory potential of individuals’ overall diet across varying populations and dietary assessment methods . There a < 0.01)  and in t < 0.01) . Apart f < 0.01) ,29,59,60There are several theories to explain the association between the DII and CRC risk; one of the most commonly considered is the effect of pro-inflammatory diet on insulin resistance through increasing systemic inflammation . AnotherDietary factors can be related to CRC through mechanisms other than inflammation. For example, consumption of red and processed meat increases the risk of CRC through increased levels of the haem iron content , N-nitroThis meta-analysis had some limitations. First, DII score for all the studies was based on self-reports collected from food frequency questionnaires, which are not error-free. We suspect that self-assessments using these instruments in case-control studies are encumbered by recall bias , which cIn conclusion, this meta-analysis suggests that a more pro-inflammatory diet, as estimated by the higher DII score, was independently associated with an increased risk of CRC. Hence, promoting diets low in pro-inflammatory items and rich in anti-inflammatory food components should help in reducing the incidence of CRC. Future research should concentrate on how DII fares in a population with CRC and what effect it would have on CRC-specific mortality.


So, we performed this updated meta-analysis and tried to give a more precise estimation of association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility.Studies investigating the association between the MTHFR gene 1298A>C polymorphism and breast cancer susceptibility was assessed using odds ratio (OR) and corresponding 95 % confidence interval (95 % CI). The meta-analysis was performed using Stata 11.0 software.Relevant studies published before 1 January 2016 were identified by searching PubMed and EMBASE. The strength of relationship between the P = 0.218; recessive model: OR = 1.00, 95 % CI 0.97–1.02, P = 0.880; homozygote genetic model: OR = 0.99, 95 % CI 0.98–1.01, P = 0.390; heterozygote genetic model: OR = 0.99, 95 % CI 0.97–1.00, P = 0.138; and allele contrast genetic model: OR = 0.99, 95 % CI 0.98–1.01) for MTHFR gene 1298 A>C polymorphism and breast cancer susceptibility. In the subgroup analysis stratified by source of control, decreased risk of breast cancer was found in studies with hospital-based controls in dominant model .A total number of 38 case-control studies including 18,686 cases and 22,299 controls were identified. No association was found in five genetic models (dominant model: OR = 0.99, 95 % CI 0.99–1.00, MTHFR gene 1298A>C polymorphism and breast cancer susceptibility for overall population.Our meta-analysis suggested that there is no significant association between  BRCA1) gene were suggested to be linked with high incidence of breast cancer in some families [methylenetetrahydrofolate reductase (MTHFR) gene has been widely studied.Breast cancer is the most frequently diagnosed cancer among women, which contributed to 25 % of all cancer cases in women worldwide, and it is the leading cause of female cancer-related death . In UK, families . Since tMTHFR locus locates on chromosome 1 at the end of short arm (1p36.6), which encodes enzymes relevant to folates metabolism. The enzyme encoded by MTHFR gene takes part in the irreversible conversion of 5,10-metylenetetrahydrofolate to 5-methyltetrahydrofolate, which plays a crucial role in homocysteine remethylation to methionine [MTHFR gene participate in the folate-metabolizing genetic pathway and are fundamental during the synthesis, repair, and methylation process of DNA, RNA, and protein, which may affect folate and vitamin B12 level [1298A>C polymorphism is caused by A to C transition in exon 7 and results in alanine in substitution of glutamine at codon 429 of the protein [MTHFR 1298A>C genetic polymorphisms have higher plasma level of homocysteine [The thionine . Previou12 level , 10. Of  protein . SubjectMTHFR gene 1298A>C polymorphism and breast cancer risk. However, the results are inconsistent, with some studies found significant association [MTHFR gene 1298A>C polymorphism and breast cancer susceptibility.Many studies have investigated the association between ociation , 14, whiociation , 16. Altociation , recentlociation –20. In oMTHFR gene 1298A>C polymorphism until January 1, 2016. Searching terms were “breast cancer” or “breast neoplasm”, in combination with “methylenetetrahydrofolate reductase” or “MTHFR” or “MTHFR A1298C” or “MTHFR 1298A>C” or “rs1801131” or “Glu429Ala”, and in combination with, “polymorphism” or “variant” or “genotype” or “allele”. We also hand-checked the reference lists of all the included studies to make sure no study was missed. Two researches conducted the searches independently. If several publications carried out among same patients and controls, we only included one study with the most complete data.Two databases were electronically searched, including PubMed and EMBASE, to retrieve studies analyzing the association between breast cancer susceptibility and MTHFR gene 1298 A>C polymorphism and breast cancer susceptibility; (3) breast cancer was pathologically confirmed for all of the patients; (4) sample sizes and individual genotype frequencies in cases and controls were available; and (5) cases and controls should be matched.We first performed initial screening of titles and abstract. A second round screening was based on full-text reviews. Studies were considered eligible if they met the following criteria: (1) it was a case-control study in design; (2) it evaluated the Researches were excluded if they met any one of the following criteria: (1) data came from reviews or abstracts; (2) genotype and allele frequencies were both unavailable; (3) subjects with other malignant tumor were included in controls; (4) repeatedly published literature; (5) not breast cancer susceptibility outcome; and (6) controls were chosen from women with a family history of breast cancer or with other kinds of malignant tumors.MTHFR gene 1298A>C polymorphism, and information of Hardy-Weinberg equilibrium (HWE) in control groups. Different ethnicity descents were categorized as Caucasian, Asian, African, and if studies were with more than one ethnicity, they were categorized as mixed ethnicity.Two reviewers independently searched and selected literature, and then, extracted relevant data according to a data extraction form. Disagreements were solved by discussion until consensus was made. The extracted data including the first author, year of publication, country of origin, ethnicity of the study population, source of control, sample size, the genotype and allele frequencies of the For each included study, the quality assessment was conducted according to the STrengthening the REporting of Genetic Association (STREGA) studies). If the study met all or most of the criteria in this approach, it would be classified as “++” or “high quality”. For study in which some of the criteria were fulfilled and the others were not likely to change the results and conclusions, it would be graded as “+” or “moderate quality”. For studies fulfilled few or no criteria and the results were thought to be with non-ignorable bias, it would be classified as “−” or “low quality” .www.stata.com). Odds ratio (OR) and its corresponding 95 % confidence intervals (95 % CI) were used to evaluate the strength of association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility. Heterogeneity among included studies was tested using chi-square-based Q test and I2 test. Phet < 0.05 or I2 > 50 % were considered as statistically significant for heterogeneity. The Mantel-Haenszel method was used for fix-effect model if no heterogeneity was found. Otherwise, the DerSimonian-Laird random-effect model was used. Fix-effect model considers that across all studies, the genetic factors have similar effects on genetic disorder susceptibility and the observed differences among studies are caused just by chance [MTHFR gene 1298A>C polymorphism and breast cancer susceptibility. We assessed the dominant model (AA + AC vs. CC), recessive model (AA vs. AC + CC), allele contrast genetic model (A vs. C), the heterozygote comparison (AC vs. CC), and the homozygote comparison (AA vs. CC). P < 0.05 showed the statistical significance. HWE was tested for included studies if no relevant information was provided in original research. Sensitivity analyses were conducted by omitting individual studies sequentially. Moreover, we performed subgroup analysis stratified by ethnicity, source of control, and deviation from HWE. Publication bias was quantitatively assessed by Egger’s linear regression test [Data analysis was conducted using STATA 11.0 software  and OR was 0.99 (95 % CI 0.99–1.00), suggesting that no association was found in the dominant model. The Egger’s linear regression test indicated that there was some evidence of publication bias in this model . Other four genetic models were also performed (Table P = 0.037), but not in allele contrast genetic model    Table . Figure MTHFR is an essential gene in the one-carbon metabolism pathway. During the past few years, many meta-analyses assessing the association between MTHFR gene polymorphism and cancer risks have been published, including liver cancer, ovary cancer, lung cancer, gastric cancer, pancreatic cancer, cervical cancer, and esophageal cancer [MTHFR gene 1298A>C polymorphism and breast cancer susceptibility has existed for a long time. In 2002, Sharp et al. for the first time published a case-control study estimating the association between MTHFR gene 1298A>C polymorphism and breast cancer risk. Their result suggested that risk was significantly lower for the 1298CC genotype compared to AA genotype  [6 and B12 [l cancer –60. Gene06–0.97) . However06–0.97) , this fu06–0.97) , dietary and B12 , physica and B12 , long-te and B12 , and hor and B12 , are posMTHFR gene 1298A>C polymorphism and breast cancer susceptibility for overall population, with ORs from 0.99 to 1.00 and narrow 95 % CIs for all of the five genetic models. Moreover, in our study, no association was found in different ethnicities or in population-based studies, which thereby strengthened this association. As shown in our meta-analysis, studies with hospital-based design or controls deviated from HWE had a weak, but statistical significant decreased association with breast cancer in dominant model. However, in these two kinds of studies, the controls may not represent the whole population and thereby, the results from them should be interpreted with caution. Overall, our meta-analysis based on 38 case-control studies provided reliable and comprehensive estimations. The association in the five genetic models sustained unchanged in the sensitivity analysis, which further confirmed the results of main analysis.Our study has important strengths. All original studies used a case-control study design, which is a useful tool to identify gene and disease associations. However, individual genotype case-control studies could not be based on a large number of subjects or contain patients in different ethnicities, and thus has insufficient statistical power. Our meta-analysis based on case-control studies involving 40,985 subjects brings to light that there is no significant association between P value for heterogeneity was less than 0.05, indicating significant heterogeneity among the included studies. Finding the potential sources of heterogeneity is an important part of meta-analysis, which can greatly influence the results of the research. To detect the possible source of heterogeneity in our meta-analysis, we performed the subgroup analysis stratified by ethnicity, source of control, and deviation from HWE. When stratified by ethnicity and source of control, the heterogeneity was significantly decreased in Asian and population-based subgroups. Therefore, the different ethnicity and source of control may contribute to the overall heterogeneity. However, heterogeneity still existed in Caucasian, mixed ethnicity, and hospital-based control subgroups, suggesting that ethnicity and source of control did not fully explain the heterogeneity among studies. Further studies may try to explore in interactions between different factors and to minimize the heterogeneity in subgroups.It is also important to mention the heterogeneity existed in this study. For all genetic models in the main analysis, MTHFR gene polymorphisms and breast cancer susceptibility, and the majority of them concerned on 677C>T polymorphism [1298A>C polymorphism [Several previous meta-analyses have been published to analyze the association between morphism –69. Two morphism , 70. TheMTHFR gene 1298A>C polymorphism and breast cancer susceptibility. Different characteristics in study population and study design may contribute to the heterogeneity. Considering that meta-analysis is a kind of retrospective research and may easily be affected by methodological deficiencies of the included studies, we developed a detailed protocol before conducting this analysis, to ensure the quality of our research.We should also pay attention to the several limitations in our study, which may affect the result. Firstly, we only included published studies meeting our inclusion criteria from two databases, similar studies in other databases and unpublished researches may have been missed, and this is also the main reason for the publication bias we found in four of the five genetic models. Secondly, the control groups in some of the included studies were deviated from HWE, which may fail to represent the whole population and have some effects on the overall estimation. Thirdly, although the results from subgroup and sensitivity analyses were quite similar to the main analysis, significant heterogeneity was detected in all five genetic models of MTHFR gene 1298A>C polymorphism and breast cancer susceptibility for overall population.From the combination results of currently included studies, our meta-analysis suggested that there is no significant association between


DLG5 R30Q (rs1248696) and P1371Q (rs2289310), but the results remain controversial. We conducted a meta-analysis including a total of 22 studies with 10,878 IBD patients and 7917 healthy controls for R30Q and 5277 IBD cases and 4367 controls for P1371Q in order to systematically assess their association with the disease. The results indicated that R30Q was significantly associated with reduced susceptibility to IBD in Europeans by allelic and dominant comparisons, but not in overall population. No significant association was found between R30Q and Crohn’s disease (CD) or ulcerative colitis (UC). P1371Q was associated with increased risk of IBD in Europeans and Americans. On the contrary, a decreased risk of IBD was observed in Asian population for P1371Q. In disease subgroup analysis, we found that P1371Q was also significantly associated with CD, but this relationship was not present for UC. In conclusion, our results strongly suggest that the both polymorphisms of DLG5 are correlated with IBD susceptibility in an ethnic-specific manner. Additional well-designed studies with large and diverse cohorts are needed to further strengthen our findings.Growing evidence from recent studies has demonstrated an association between inflammatory bowel disease (IBD) susceptibility and two polymorphisms of  NOD2)5ATG16L1)(STAT3)8IRGM)IL23R)11Inflammatory bowel disease (IBD) is a relapsing and chronic inflammatory disorder mainly affecting the small intestine and colon23DLG5) gene, a member of the membrane associated guanylate kinase (MAGUK) family, encodes a cell scaffolding protein, which is wildly expressed in human tissues including liver, heart, pancreas, small intestine and colon131315DLG5 relating to IBD in a German cohort1718et al. reported that the both variants of DLG5 were associated with increased risk for IBD, additional studies replicated the association in different populations162022232425262728Discs large homolog 5 , heterozygote model  and dominant model . Therefore, random effects model was applied in these analyses. No significant association was identified between R30Q and IBD in overall population . Nevertheless, a trend of reduced risk could be seen  and dominant model  by fixed-effect model because no significant statistical heterogeneity was identified . However, no association was observed for the other three genetic models. As for the American and Australasian populations, no significant correlation was found in either cohort (data not shown).Intriguingly, subgroup analysis based on ethnicity disclosed a significant correlation between R30Q and IBD susceptibility in Europeans in allelic model  were analyzed. However, no modifying effect of R30Q on the risk of UC or CD was discovered in any genetic model .P = 0.01), and in Europeans in homozygote comparison  and recessive comparison  using fixed-effect model. However, we observed an opposite relationship between P1371Q and IBD in Asian cohort   . ConsideP = 0.02; dominant model AA + CA vs. CC: OR = 0.80, 95%CI: 0.68–0.95, P = 0.01) by fixed-effect model . In addition, a significant statistical association between P1371Q and CD in Asian was identified by heterozygote comparison . However, no significant association was found in Europeans or Americans . Nevertheless, R30Q was not significantly related to CD susceptibility in men (P = 0.058). In summary, they provided an evidence of a trend toward reduced CD risk in both males and females. This finding is consistent with our subgroup analysis of CD in European cohort, mainly from Caucasian. Compared to the above two publications, our meta-analysis summarized 22 eligible case-control studies with a larger sample size and offered convincing evidence by systematically analyzing the association of IBD susceptibility with two DLG5 polymorphisms, including not only the most studied variant, R30Q, but also another significant variant, P1371Q.A previous meta-analysis including 13 studies was performed to analyze the association between R30Q polymorphism and IBD risk in CaucasiansDLG51142DLG5 encodes a cell scaffolding proteins that has been found to play an important role in the determination and maintenance of intestinal epithelial cells polarityDLG5 participates in epithelial cell proliferation, migration and adhesionin silico analysis, both the R30Q and P1371Q variants probably influence or change the structure and function of DLG5DLG5 mutations might interfere with the epithelial barrier function of the intestine, and therefore be implicated in IBD pathogenesis.As a chronic and relapsing inflammatory disease, a growing number of studies have shown that IBD is associated with both genetic and environmental factors40et al.DLG5 polymorphisms were associated with IBD in a European cohort, and among them, R30Q was strongly related to an increased risk for IBD. Subsequently, several studies observed similar results2127222324262833et al. summarized R30Q data from published studies and attempted to resolve this discrepancy but failed201826283037DLG5 and IBD susceptibility.In 2004, Stoll There were several strengths of our meta-analysis. First of all, we performed the present study based on large sample sizes including a total number of 10878 IBD patients with 7917 controls on R30Q polymorphism and 5277 IBD patients with 4367 controls on P1371Q polymorphism, which helped to add convincing evidence. Compared with previous meta-analyses, more studies were included. Additionally, subgroup analysis, sensitivity analysis and genotype comparison were also carried out. Furthermore, we systematically investigated the relationship between P1371Q and IBD risk. To the best of our knowledge, this is the first meta-analysis regarding P1371Q and IBD. Moreover, we set and implemented strict inclusion and exclusion criteria to guarantee the quality of the included studies and the reliability of the results. Finally, selection bias was well-controlled via literature search, and no publication bias was identified by Egger’s test.Nevertheless, the present meta-analysis has several limitations that should be considered. Firstly, potential heterogeneity observed among the studies of both R30Q and P1371Q, which could not be effectively reduced via subgroup and sensitivity analysis, might partially influence the results. Hence, some other details are needed to analyze the sources of the heterogeneity. For instance, sample size, age of patients and genotyping methods might contribute to the heterogeneity. Secondly, there were two studies with genotypes deprived from HWE, of which one was for R30Q and the other for P1371Q. Although the pooled ORs were not significantly influenced by this study for R30Q, the significant association between P1371Q and CD was diminished by omitting the study for P1371Q. Thirdly, although we found that individuals with P1371Q variant have lower risk of suffering IBD in Asian population, the number of eligible studies and patients was limited. Therefore, many more high quality case-control studies are needed to further explore the association between P1371Q and IBD susceptibility in Asian cohorts.DLG5 R30Q polymorphism is associated with a reduced risk of IBD in Europeans, while P1371Q is associated with an increased risk in Europeans and Americans, but could serve as a protective factor in Asian population. Particularly, P1371Q may decrease the risk of CD in overall population. However, caution should be taken for P1371Q because of insufficient data and population heterogeneity, which might have impact on the convincingness of the results. Well-designed case-control studies with larger sample sizes and multiple ethnicities are required to strengthen the results of the current study. More importantly, studies focusing on the biological functions and mechanisms involving the IBD pathogenesis of DLG5 are also urgently needed.In summary, despite the limitations above, our results suggest that the DLG5 polymorphisms (R30Q and P1371Q) and IBD risk in the Pubmed and Web of Science up to March 14, 2016. The following search terms were used: (inflammatory bowel disease OR IBD OR ulcerative colitis OR UC OR Crohn’s disease OR CD) and (genetic polymorphism OR polymorphism OR variant) and (DLG5 OR discs large homolog 5), without any limitation. Manual search was also performed to obtain additional publications through the reference lists of retrieved studies and reviews.Two independent investigators conducted a literature search for relevant studies evaluating the relationship between DLG5 R30Q or P1371Q polymorphism and IBD risk; (3) provided detail genotype or allelic distribution; (4) contained sufficient data to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Exclusion criteria: (1) reviews, meeting articles, laboratory studies or duplication of previous publications; (2) studies without detail genotype data; (3) researches did not focus on DLG5 R30Q or P1371Q polymorphism; (4) family-based studies. When there were several articles about a study or the same cohort included in two or more publications were identified, only the latest or complete study was selected.Studies meeting the following criteria were included: (1) cases-control study; (2) evaluation the association between The following information was independently extracted by two authors from eligible studies: name of the first author, year of publication, country and ethnicity of the study population, genotyping method, number of cases and controls, allele and genotype frequency in cases and controls. Any disagreement was resolved by discussing with a third author to reach a consensus.DLG5 R30Q and P1371Q variants and IBD risk. Meta-analyses were performed by allelic model , heterozygote model , homozygote model , dominant model , recessive model . Cochran’s Q statistic and I2 test were performed to evaluate the heterogeneity among the eligible studies. Statistical heterogeneity was defined as P < 0.1 or I2 > 50%. Random effects models or fixed-effect model was used to pool the effect size depending on the existence of statistical heterogeneity or not, respectively. Chi-square test was applied to evaluate the Hardy-Weinberg equilibrium (HWE) in control group. Publication bias was detected by Egger’s test. All the P value were two-sided and P < 0.05 was considered statistically significant. All statistical analyses were performed by Review Manager software version 5.2 and Stata software version 12.0 .The present meta-analysis was conducted according to the PRISMA checklists and following the guidelineHow to cite this article: Li, Y. et al. Meta-analysis of associations between DLG5 R30Q and P1371Q polymorphisms and susceptibility to inflammatory bowel disease. Sci. Rep.6, 33550; doi: 10.1038/srep33550 (2016).


The present study suggests that excessive maternal BMI is associated with increased ASD risk in offspring.Controversial results of the association between maternal body mass index (BMI) and risk of autism spectrum disorder (ASD) in offspring were reported among several studies. This meta-analysis was conducted to estimate the overall association between maternal BMI and risk of ASD in offspring. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched until January 2016. Cohort and case-control studies addressing the association between maternal BMI and risk of ASD in offspring were included. We used random-effect models to estimate the summary relative risks (RRs), we also performed a dose-response meta-analysis to estimate the trend from the correlated log RR estimates across levels of BMI quantitatively. Totally, 6 cohort studies and 1 case-control study involving 8,403 cases and 509,167 participants were included for analysis. The summary RR  for ASD in offspring in relation to maternal underweight, overweight, and obesity vs. normal weight during pre-pregnancy or pregnancy, was 1.07 , 1.28  and 1.36 , respectively. A linear dose-response relationship was found, with a pooled RR of 1.16  for each 5 kg/m After removal of duplicate literatures, 1123 articles were left for screening. From screening the titles and abstracts, 1111 articles were excluded as they were not clearly relevant. After evaluating the full text of the remaining 12 literatures, we further excluded 5 studies11121314789141617I2 = 0.0%, P = 0.929), low heterogeneity  and high heterogeneity  observed across studies, respectively , the pooled RR  of ASD was 1.07 0.93, 1.23), 1.28  and 1.36  for children born to mothers with underweight, overweight and obesity, with low heterogeneity . Compared with children born to mothers in normal weight, the pooled RR for ASD in offspring was 1.16  for each 5 kg/m2. increment in maternal BMI .There was no evidence of significant publication bias among the included studies according to Begg’s test and Egger’s test  during pre-pregnancy or pregnancy on ASD risk in offspring. Compared with children whose mothers were at normal weight, children born to overweight and obese mothers have a 28% and 36% higher risk of developing ASD, respectively. Maternal underweight was not associated with increased ASD risk. A linear dose-response relationship was found, with the risk of ASD increasing by 16% for each 5 kg/mAlong with the nearly doubled world’s obesity rate between 1980 and 2008, the prevalence of ASD has also been increasing rapidly during the same period. While elevated awareness and updated diagnostic criteria of ASD might contribute to its increased prevalence, it is possible that the obesity epidemic may also play a role, which is supported by the results of our meta-analysis. The present findings provide strong persuasion for women to keep appropriate weight during pre-pregnancy or pregnancy, so as to reduce ASD risk in their offspring.Although the causal pathway remains to be elucidated, the effects of maternal BMI on ASD may be explained by several hypothesizes. Of the proposed mechanisms, inflammation is the most frequently mentioned one to explain the association of maternal BMI and ASD. It is observed that obese women had higher levels of C-reactive protein in the plasma compared with normal weight pregnant women22Obesity is a significant risk factor for diabetes, while maternal diabetes itself significantly increase the risk of ASD in the offspring242527This meta-analysis was based on observational studies. Therefore, we cannot exclude potential biases due to other factors which may contribute to ASD. For instance, mothers who have lower BMI will probably have more healthy lifestyles, such as more physical exercise, less intake of salt and saturated fat, and thus they are less likely to be affected by hyperglycemia and diabetes than those who have higher BMI. Although all studies controlled for several factors, including maternal age at baseline, race, child’s sex, and birth year etc, the potential influences from residual or unmeasured confounding cannot be ruled out.et al.et al.Apart from maternal BMI, paternal obesity was also suggested to be associated with risk of autism in offspring. In two included studies, Gardner Two recent studies8et al.Maternal BMI were self-reported without objective ascertainment in 3 included studies9173279141617Our meta-analysis included 2 retrospective studies72 increment in BMI is associated with 16% increased ASD risk. Considering the limited small number of included studies, further well-designed studies are needed to confirm the our findings.In conclusion, the present study suggests that excessive maternal BMI is associated with an increased ASD risk in offspring. Approximately, every 5 kg/mWe conducted a literature search of PubMed, Embase, Web of Science, and Cochrane Library up to 29 January 2016 for case-control and cohort studies examining the association between maternal BMI and risk of ASD in offspring. The search terms for PubMed were: (body mass index OR overweight OR obesity) AND autism. Similar search strategies were used in other databases. In addition, we screened references list from relevant original papers and review articles to identify further pertinent studies. We applied no language restriction in the process of literature search and selection. Two researchers independently conducted the literature search and disagreement was solved by discussion. The Meta-Analysis of Observational Studies in Epidemiology guidelinesStudies were included in the meta-analyses if they were case-control or cohort studies which reported the association between maternal BMI and risk of ASD in offspring. To be included, studies had to have available results as an odds ratio (OR) or a relative risk (RR) with corresponding 95% confidence interval (CI), or sufficient data to calculate them. Non-human studies, case reports, conference abstract, review and studies that with insufficient data were excluded.The following data were extracted from each study: name of the first author, publication year, study name and period, study location, characteristics of participants (sex and age), number of cases and participants, the RRs or ORs with corresponding 95% CIs, confounding factors that being adjusted for in the analysis. We also extracted dose-relationship data for maternal BMI and ASDs risk, including the number of cases and participants (or person-years) and RR (95% CI) for each category of BMI.The Newcastle-Ottawa Scale (NOS)P I2 statistics37I2 values of 25%, 50%, and 75%, was considered to be low, moderate, and high degrees of heterogeneity, respectivelyTo take into account heterogeneity between studies, a random-effects model was used to calculate summary RRs and 95%CI for non-reference  versus the reference  categories of BMI and for the dose-response analysis. The odds ratios (ORs) were considered equivalent to RRs considering that ASDs were sufficiently rare. Heterogeneity between studies was assessed by using Q statistics  was used to analyze the data, and the significance level was set as 0.05 where otherwise specified.A 2-stage random-effects dose-response meta-analysis was used to examine the potential trend between maternal BMI and risk of ASD42How to cite this article: Wang, Y. et al. Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis. Sci. Rep.6, 34248; doi: 10.1038/srep34248 (2016).


Objective. Type 2 deiodinase (Dio2) is an enzyme responsible for the conversion of T4 to T3. The Thr92Ala polymorphism has been shown related to an increased risk for developing type 2 diabetes mellitus (T2DM). The aim of this study is to assess the association between this polymorphism and glycemic control in T2DM patients as marked by the HbA1C levels. Design and Methods. The terms “rs225014,” “thr92ala,” “T92A,” or “dio2 a/g” were used to search for eligible studies in the PubMed, Embase, and Cochrane databases and Google Scholar. A systematic review and meta-analysis of studies including both polymorphism testing and glycated hemoglobin (HbA1C) assays were performed. Results. Four studies were selected, totaling 2190 subjects. The pooled mean difference of the studies was 0.48% , indicating that type 2 diabetics homozygous for the Dio2 Thr92Ala polymorphism had higher HbA1C levels. Conclusions. Homozygosity for the Dio2 Thr92Ala polymorphism is associated with higher HbA1C levels in T2DM patients. To confirm this conclusion, more studies of larger populations are needed. Type 2 deiodinase (Dio2) is localized on the long arm of the 14th human chromosome in 14q24.3. It is an intracellular enzyme which catalyzes the conversion of thyroxine (T4) to its active form triiodothyronine (T3) [ Dio2 gene (A/G) results in a threonine change to alanine (Thr92Ala) at codon 92 [ Dio2 Thr92Ala polymorphism has been reported to be associated with many disorders, such as osteoarthritis [ Dio2 Thr92Ala polymorphism is associated with glycemic control in T2DM patients as marked by the HbA1C level.A single nucleotide polymorphism in therthritis , 4, hyperthritis , Graves'rthritis , Kashin-rthritis , bipolarrthritis , depressanine Thr2Ala at crthritis , 11. In rthritis –18. HoweA literature search was conducted by two investigators (Xiaowen Zhang and Jie Sun) in February 2016, using the PubMed, Embase, and Cochrane databases and Google Scholar. The terms Thr92Ala, T92A, rs225014, and Dio2 a/g were used. Reference lists in the articles and recent reviews were also searched. Dio2 polymorphism and (2) including T2DM patients along with their respective glycated hemoglobin (HbA1C) levels.Studies were selected for meta-analysis if they met the following criteria: (1) being observational studies related toThe following data were extracted from selected studies: name of first author, year of publication, country, age, gender, duration of diabetes, treatment, population size, and HbA1C means and standard deviations (SD) of each genotype. The difference between genotypes was analyzed in both recessive and dominant inheritance model.Two investigators (Yaqiu Jiang and Wenqing Han) assessed the quality of the selected studies using the Newcastle-Ottawa Scales (NOS) . Informahttp://dx.doi.org/10.1155/2016/5928726). Review Manager 5.3 was used for data analysis. The mean differences and the 95% confidence intervals (95% CI) for each study and for the pooled effect were calculated to evaluate the relationship between Thr92Ala polymorphism and HbA1C value in T2DM patients. Heterogeneity was assessed using the Q statistical test and I2 statistic. A sensitivity analysis was performed by sequential omission of each study. Subgroup analysis was processed to investigate heterogeneity in the meta-analysis.This systematic review was conducted according to the recommendations outlined in the PRISMA  and I2 statistic (I2 = 52%) showed moderate heterogeneity; therefore, a random effects model was used. Sensitivity analyses by sequential omission of each study resulted in similar results, with calculated MDs of 0.44% , 0.60% , 0.33 , and 0.55% , respectively.When analyzed in a recessive inheritance model, the meta-analysis of 4 studies including data on the association between Thr92Ala polymorphism and HbA1C levels showed that the mean difference (MD) was 0.48%  , indicat Dio2 Thr92Ala allele were not higher. Both the Q statistical test (P = 0.69) and I2 statistic (I2 = 0%) showed no heterogeneity; therefore, a fixed effects model was used. Sensitivity analyses by sequential omission of each study resulted in similar results, with calculated MDs of 0.06% , −0.01% , and 0.13% , respectively.When analyzed in a dominant inheritance model, one study was excluded because Thr/Thr and Ala/Thr genotypes were grouped and compared with Ala/Ala genotype . The metIn order to uncover the source of heterogeneity, subgroup analysis was performed . Dhanunj Dio2 Thr92Ala polymorphism and glycemic control in T2DM patients have been contradictory [ Dio2 Thr92Ala polymorphism on HbA1C levels in T2DM patients.The results of the previous studies regarding the association between theadictory , 20, 21.Some studies assumed that it is a recessive inheritance model because of “Thr/Thr and Thr/Ala genotypes showing similarities in biochemical characteristics” , 20. Howhttps://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/). Subgroup analysis shows that Dhanunjiya's study, which was different in BMI or race from the other 3 studies, would be the reason for moderate heterogeneity. Both BMI and race might have apotential impact on the HbA1C levels in T2DM patients. Further studies are needed to investigate these potential influential factors.Among the four included studies, three were conducted in Brazil, thus related to Brazilian population , 14, 21, Dio2 Thr92A and peroxisome proliferator-activated receptor-gamma2 (PPARγ2) Pro2Ala polymorphisms interact in the modulation of systolic and diastolic blood pressure and metabolic syndrome [β3-adrenergic receptor Trp63Arg results in an increased BMI, indicating a synergistic effect of these two polymorphisms [Carriers of the Ala allele have been shown to have a net decrease in glucose disposal . The Diosyndrome . Furtherorphisms . in vitro, indicating that Thr92Ala may be a marker, rather than a functional polymorphism of the decreased enzyme velocity.Some studies have shown that the Thr92Ala polymorphism is related to type 2 diabetes mellitus (T2DM), insulin resistance. However, the Framingham Heart Study showed that there is no association of Thr92Ala polymorphism with T2DM or hypertension risks , 24. ThoThe limitations of this meta-analysis are as follows: (1) T2DM is a heterogeneous disease , and thu Dio2 Thr92Ala polymorphism might be associated with worse glycemic control in type 2 diabetics as marked by the HbA1C levels. Further epidemiological studies of larger populations from different geographic regions are needed.In conclusion, homozygosity for theThis review protocol has been prepared according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097


Leptin receptor (LEPR) Gln223Arg gene polymorphism has been associated with an increased susceptibility to Type 2 diabetes mellitus (T2DM). Results from various studies, however, are inconsistent.The LEPR Gln223Arg gene polymorphism with T2DM in the Chinese population, a meta-analysis of 3,367 subjects from seven independent studies was performed. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) were evaluated by the fixed-effects model.To better elucidate the association of LEPR Gln223Arg gene polymorphism and T2DM in the Chinese population was found under allele , dominant , recessive , heterozygous , and homozygous  genetic models.A significant relationship between LEPR Gln223Arg gene polymorphism was associated with an increased risk of T2DM in the Chinese population. Therefore, Chinese carriers of the G allele of LEPR Gln223Arg gene polymorphism may be more susceptible to T2DM than the general population. The most recent survey from the Chinese Diabetes Society shows that the overall prevalence of diabetes mellitus (DM) has increased to 11.6% in the Chinese adult population, making the number of DM patients in China 114 million. This suggests that China, as a country, has the most DM patients in the world [neuropeptide Y (NPY) gene product, ultimately reducing insulin secretion. Leptin also binds with leptin receptor (LEPR) located on pancreatic beta cells to regulate insulin secretion [Leptin is peptide hormone secreted by adipose tissue and while it is most famous as the mediator for the sensation of satiety, it also helps regulate energy metabolism and body lipid homeostasis. It also regulates insulin secretion through two distinct mechanisms. It concurrently inhibits parasympathetic nervous system and excites the sympathetic by inhibiting the expression of ecretion , 3.LEPR gene, located on the chromosome 1p31, spans more than 70 kb, contains 20 exons and 19 introns, and encodes for 1165 amino acids. Though there are many mutations and polymorphisms in the human LEPR gene, the polymorphisms sites have been limited almost exclusively to the 20 exons of the LEPR gene. The Gln223Arg gene polymorphism specifically is caused by the substitution of the adenine at the 668th position by a guanine, mutating the 223rd amino acid, an arginine, to be replaced by a glutamine. This mutation is located on the 6th exon of the protein and may impair signal transduction enough to increase susceptibility to T2DM [The  to T2DM .LEPR Gln223Arg gene polymorphism and T2DM have been conducted in the Chinese population, results are contradictory. In 2009, Ying et al. reported the A allele of LEPR Gln223Arg gene polymorphism to be associated with an increased risk of T2DM [LEPR Gln223Arg gene polymorphism to be a risk factor for the T2DM in 2011[Although many studies on the relationship between the  of T2DM . In contM in 2011. Shi et M in 2011.LEPR Gln223Arg gene polymorphism and T2DM in the Chinese population.In the current meta-analysis, data from 2,084 T2DM patients and 1,283 controls was analyzed to further elucidate the relationship between LEPR Gln223Arg gene polymorphism. Among the ten included studies, three studies deviated from the HWE [Publication years of the included studies ranged from 2002 to 2014 . Of the 16 papers retrieved by the initial search, seven met inclusion criteria. Among the nine excluded studies, three studies were excluded due to control groups that deviated from Hardy-Weinberg equilibrium (HWE). Three studies were reviews and an additional three studies did not analyze either T2DM or the  the HWE –10 , dominant , recessive , heterozygous , homozygous . No significant heterogeneity was detected under all five genetic models (P>0.05)  , dominant (OR: 1.466), recessive (OR: 0.539), heterozygous (OR: 0.700), and homozygous (OR: 0.472) genetic models. The fixed genetic model was used exclusively due to the lack of heterogeneity between studies. We, therefore, concluded that the Chinese individuals with the G allele of LEPR Gln223Arg gene polymorphism may be predisposed to T2DM.In the current meta-analysis, we observed a significant association between the LEPR gene is also called T2DM gene.T2DM is a polygenic disease which is closely related with obesity, hypertension, gout, and lipid metabolism disorder. T2DM is clinically called insulin resistance (IR) syndrome, the core of which is the IR. Recently many studies have shown that the leptin resistance might still exist in the IR patients at the same time . Leptin What mechanisms can explain the increased risk of T2DM associated with this polymorphism? One possible mechanism is that the glutamine residue may cause reduced LEPR expression on the plasma membrane impairing signal transduction through the receptor. It also could increase risk of T2DM by influencing neurological function of the vagus nerve.The vagus nerve sensibility for the insulin secretion were reduced and further led to the IR, disrupting, not only glucose metabolism, but also fat metabolism. The IR not only makes the glucose metabolism disturbance, but also the fat metabolism disturbance. Although these mechanisms have yet to be demonstrated physiological, they provide a plausible rationale for the results from this study .LEPR Gln223Arg gene polymorphism and T2DM in 2015 and 2016, respectively [LEPR Gln223Arg gene polymorphism had no effect on the susceptibility with T2DM. Both of these papers, however, do not take into account differences in ethnicity. Liu’s meta-analysis grouped all Asians, including Koreans, Indians, Malaysia, and Chinese in to a single subgroup while Su’s meta-analysis analyzed data that combined Asians and Europeans. These meta-analyses also included studies with the controls’ genotype number that deviated from HWE, such as individual studies by Zhang, Zhao, and Liu [Liu et al and Su et al. both performed meta-analysis on the association between ectively . They bo and Liu –10. ThesLEPR Gln223Arg gene polymorphism. It also fails to take into account other possibly significant factors that play a role in determining plasma LEPR levels [Our study is not without limitations, however, as our results do not replace the need for more large-scale studies on the association of T2DM with R levels .LEPR Gln223Arg gene polymorphism and increased T2DM risk in the Chinese population. Chinese carriers of the G allele of LEPR Gln223Arg gene polymorphism may be more susceptible to T2DM. This conclusion clarifies the mixed results on the topic and develops our understanding of T2DM so that in the future, we can develop personalized treatment strategies for our patients. Taking account the above mentioned limitations, more research is required to verify this conclusion.In conclusion, we found a significant association between the The keywords LEPR, Q223R or Gln223Arg, rs1137101, T2DM, diabetic, and diabetes were searched in on PubMed, the Web of Science, Embase, the China National Knowledge Infrastructure, the China Biological Medicine Database, the VIP database, and the Wanfang database.LEPR Gln223Arg gene polymorphism and T2DM b) diagnose T2DM based on criteria determined by the World Health Organization in 1999  c) be case-controls or cohort studies published in official journals d) have a control group whose genotype is at HWE. e) have cases where allele and genotype frequencies and their corresponding controls were available.In order to meet inclusion criteria, the paper had to a) evaluate the association between LEPR gene Gln223Arg polymorphism with other related conditions, such as Type 1 diabetes mellitus, obesity, or hypertension, were excluded. Participants with diseases of the heart, liver, kidney, and the urinary tract were also excluded. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included studies.Studies that evaluated the association of Included data was abstracted through a standardized protocol of three researchers. Two researchers identified studies for inclusion independently, while a third acted as a mediator to resolve any disagreements between the two. Studies that violated the inclusion criteria, were published repeatedly, or lacked adequate data were rejected. Data sets used by the same authors for multiple papers were included in our analysis once. Table LEPR Gln223Arg gene polymorphism with T2DM was evaluated using odds ratio (OR) and their corresponding 95% confidence intervals. Heterogeneity between the individual studies was calculated by the Chi-square-based Q-test [Statistical analysis was performed using STATA 12.0 software . Five genetic models, allelic , dominant (GG vs. GA+AA), recessive (AA vs. GA+GG), homozygous (AA vs. GG), and heterozygous genetic models (GA vs. GG) were adopted for the current meta-analysis. The association of d Q-test . Due to d Q-test . Z-test d Q-test .


IL-10 gene with cancer susceptibility in the Chinese population, but the results remain inconclusive. To gain a more precise estimation of this potential association, we conducted the current meta-analysis based on 53 articles, including 26 studies with 4,901 cases and 6,426 controls for the -1082A/G polymorphism, 33 studies with 6,717 cases and 8,550 controls for the -819T/C polymorphism, and 42 studies with 9,934 cases and 13,169 controls for the -592A/C polymorphism. Pooled results indicated that the three promoter polymorphisms in IL-10 gene were significantly associated with an increased overall cancer risk in the Chinese population. Stratification analysis showed that the association was more pronounced for hepatocellular carcinoma and low quality studies for the -1082A/G polymorphism, lung cancer and oral cancer for the -819T/C polymorphism. However, the -592A/C polymorphism was associated with a statistically significant increased risk for lung cancer, oral cancer, hospital-based studies and low quality studies, but a decreased risk for colorectal cancer. We further investigated the significant results using the false-positive report probability (FPRP) test. Interestingly, FPRP test results revealed that only IL-10 -1082A/G polymorphism was truly associated with an increased overall cancer risk. In the subgroup analysis, only the low quality studies, lung cancer and colorectal cancer remained significant at the prior level of 0.1. Although this association needs further confirmation by considering large studies, this meta-analysis suggested an association between IL-10 gene polymorphisms and cancer risk in the Chinese population.Numerous studies have examined the associations of three promoter polymorphisms  in  Cancer is still a global public health problem. According to the GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide . AccumulIL-10 gene polymorphisms could influence cancer susceptibility.Interleukin-10 (IL-10) is an anti-inflammatory cytokine with both immunosuppressive and immunostimulatory activities . AlthougIL-10 gene is located on chromosome 1q31-32, and is composed of five exons and four introns. IL-10 gene promoter region is highly polymorphic, and three promoter single nucleotide polymorphisms (SNPs) such as -1082A/G (rs1800896), -819T/C (rs1800871) and -592A/C (rs1800872) have been reported to regulate IL-10 expression . In the subgroup analysis, a statistically significant association was found for hepatocellular carcinoma  and low quality studies .The main results regarding the association between IL-10 -819T/C polymorphism and cancer risk are shown in Table IL-10 -819T/C polymorphism and overall cancer risk . In the subgroup analysis, a statistically significant association was found for lung cancer  and oral cancer .The overall results regarding the association between IL-10 -592A/C polymorphism and cancer risk are shown in Table IL-10 -592A/C polymorphism and increased overall cancer risk . In the subgroup analysis, a statistically significant increased risk was found for lung cancer , oral cancer , hospital-based studies  and low quality studies . In contrast, a significantly decreased risk was observed for colorectal cancer .The detailed results regarding the association between IL-10 -1082A/G polymorphism and overall cancer risk , but not under the recessive model (P = 0.242) (Table P < 0.001) and -592A/C  polymorphisms. Therefore, the random-effect model was used to generate wider CIs. Sensitivity analysis was conducted and the results indicated that each individual study did not influence the pooled ORs obviously (data not shown).Substantial heterogeneities were found among all studies regarding P = 0.428; heterozygous: P = 0.395; recessive: P = 0.168; dominant: P = 0.223 and allele comparison: P = 0.179), -819T/C polymorphism , and -592A/C polymorphism .The funnel plot was symmetric for the -1082A/G Figure , -819T/CThe significant findings were assessed using the FPRP test and the results are shown in Table IL-10 gene and cancer risk in the Chinese population through 53 articles. The results revealed that all the three IL-10 gene polymorphisms we considered were associated with an increased overall cancer risk. Stratification analysis showed that the association between the -1082A/G polymorphism and cancer risk was more evident for hepatocellular carcinoma and low quality studies, the association between the -819T/C polymorphism and cancer risk was more obvious for lung cancer and oral cancer. However, the -592A/C polymorphism showed a statistically significant increased risk for lung cancer, oral cancer, hospital-based studies and low quality studies, but a decreased risk for colorectal cancer. To our knowledge, this is so far the first meta-analysis that has assessed multiple promoter polymorphisms in IL-10 gene with cancer risk in the Chinese population.In this meta-analysis, we comprehensively investigated the associations between three promoter variants  in IL-10 -1082A/G, -819T/C and -592A/C polymorphisms with overall cancer susceptibility. The study carried out by Wang et al. [IL-10 -1082A/G polymorphism, consisting 61 international studies with a total of 14,499 cases and 16,967 controls, in which no significant association was found between this polymorphism and overall cancer risk. Another meta-analysis [IL-10 -819C/T polymorphism and cancer risk, without finding any significant association between this polymorphism and overall cancer risk. The study carried out by Ding et al. [IL-10 -592C/A polymorphism, in which a decreased risk of overall cancer was found with the AA genotype. Other meta-analyses with international studies have assessed the association between polymorphisms in IL-10 gene and susceptibility to some types of cancer. For example, two studies [IL-10 -1082A/G, -819T/C and -592A/C polymorphisms with non-Hodgkin lymphoma susceptibility. Some of the significant associations found in the previous studies were not validated in our meta-analysis, for example, IL-10 -1082A/G polymorphism was associated with an increased lung cancer risk [IL-10 -592A/C polymorphism was associated with a decreased colorectal cancer risk. The discrepancy occurred because our analysis was carried out only in the Chinese population, suggesting that the polymorphisms on cancer risk might vary among different study subjects’ ethnicity or lifestyle factors.Three meta-analyses including international studies have investigated the association of analysis  including et al.  consider studies , 96 reveIL-10 -1082A/G polymorphism and overall cancer risk remained significant at the prior probability level of 0.1. In the subgroup analysis, only the low quality studies, lung cancer and colorectal cancer remained significant. Other findings were false-positive, which might be due to the limited sample size.To make our significant findings more noteworthy, FPRP analysis was performed. Interestingly, FPRP test results revealed that only the association between IL-10 -1082A/G, -819T/C and -592A/C polymorphisms and an increased overall cancer risk in the Chinese population. Second, the quality of each included study was evaluated by the quality score criteria. Third, no publication bias was detected in the study, indicating the robustness of the results. Finally, the significant findings were further validated using the FPRP test, making the results more authentic. However, some possible limitations should be considered. First, the total sample size in each individual study was less than 1000 in all but four studies [Our present meta-analysis has some highlights. First, it identified the significant association between  studies , 86, whiIL-10 gene polymorphisms and cancer risk in the Chinese population, especially for lung cancer, colorectal cancer and low quality studies. Well-designed studies with large sample size are required to verify our findings.In conclusion, this meta-analysis suggested an association between interleukin-10” or “interleukin 10” or “IL-10” or “IL 10”) AND  AND , up to 19 January, 2017. In addition, review articles and references of the selected articles were manually searched to identify additional relevant articles. Only the most recent publications or the ones with most participants were included in the final meta-analysis in cases of overlapping data.A systematic literature search was conducted in PubMed, Embase, CNKI and Wanfang database using the following MeSH terms and their synonyms:  case-control studies; (3) studies providing sufficient data for calculation of ORs and 95% CIs. Studies were excluded if any of the following aspects existed: (1) not a case-control study; (2) duplicate publications; (3) studies without available genotype data; (4) review articles, meta-analyses, conference abstracts or editorial articles; and (5) genotype frequencies in the controls departure from HWE.The inclusion criteria were as follows: (1) studies investigating the association between Two investigators independently extracted the relevant data from all included studies based on the inclusion criteria listed above. Disagreement was resolved by discussion with a third investigator. The following information was extracted from each included study: first author’s surname, publication year, cancer type, control source , genotyping methods, and number of cases and controls with different genotypes.Two independent investigators assessed the qualities of all included studies according to the criteria from a previous meta-analysis . QualityIL-10 -1082A/G, -819T/C and -592A/C polymorphisms and cancer risk was assessed by calculating the ORs and the corresponding 95% CIs. The pooled ORs were calculated for the homozygous model, heterozygous model, recessive model, dominant model and an allele comparison. The between-study heterogeneity was quantified by chi-square based Q test and the fixed-effects model (the Mantel-Haenszel method) [P > 0.1); otherwise, the random-effects model (the DerSimonian and Laird method) [The strength of association between  method)  was used method)  was adopP values were two-sided, and P < 0.05 were considered statistically significant.The FPRP was calculated to examine the significant associations found in the present meta-analysis. FPRP was calculated with 0.2 as a FPRP threshold and a prior probability of 0.1 was assigned to detect an OR of 0.67/1.50 (protective/risk effects) for an association with the genotypes under investigation . FPRP va