P < 0.05) and CV events (P < 0.05). These associations remained significant after pooling data from adjusted models . These results showed that AF is an independent risk factor for MI, CV death, and CV events.This study aimed to investigate whether atrial fibrillation (AF) predicts myocardial infarction (MI) or cardiovascular (CV) death. AF is a well-established risk factor for thrombotic stroke and all-cause mortality. PubMed, EmBase, and Cochrane Central were searched for articles comparing the incidence rates of MI, CV death, or CV events between AF and non-AF patients. Relative risk ratio (RR) was used as effect estimate. Crude and adjusted RRs were calculated. Data were pooled using a random-effects model. The meta-analysis included 27 studies. In the unadjusted analysis, AF patients had a nonsignificant trend toward a higher risk of MI compared with non-AF patients; however, a significant association was found. The crude data analysis showed that AF was associated with increased risk of CV death ( Approximately 2.7–6.1 million patients suffer from AF in the United States, a number expected to double by 20503. AF is a well-established independent risk factor for stroke, and non-valvular AF increases the risk of stroke by fivefold4. Antithrombotic medications, such as vitamin K antagonists (VKAs) and non-VKAs, are routinely recommended for AF patients to prevent stroke and systemic embolic events, while decreasing mortality6.Atrial fibrillation (AF) is the most commonly encountered clinically significant cardiac arrhythmia. It represents a major public health problem with increasing prevalence in elderly people and significant association with poor outcomes8. Multiple studies demonstrated the unfavorable prognostic impact of AF in patients sustaining MI10. The incidence of AF complicating acute MI is between 6% and 21%9. New-onset AF is associated with an increased risk of mortality even after adjusting for pivotal risk factors for AF12. AF may lead to dismal prognosis in patients with MI through adverse hemodynamic effects, including loss of atrial contraction, high ventricular rates, loss of atrioventricular synchrony, and an irregular RR interval, leading to decreased cardiac output13.Myocardial infarction (MI) has been recognized as a risk factor for new-onset AF since the Framingham Heart Study14. Indeed, AF is associated with impaired coronary flow and diminished myocardial perfusion15. Numerous studies have illustrated the associations of AF with CV outcomes17. However, controversies exist because the annual rate of MI in AF patients is low, with drug intervention in biasing the size of effect estimate19. For example,, warfarin, as a commonly prescribed drug for AF patients, may exert protective effects against MI20. Further, several studies suggested that the coexistence of atherosclerotic risk factors may contribute to increased risk of MI in AF22. Also, concerns were raised regarding the increased risk of MI after use of non-VKAs, such as dabigatran25. Thus, a systematic review and meta-analysis was conducted to compare cardiovascular outcomes between AF and non-AF patients.Previous extensive studies have emphasized more on ischemic cerebrovascular rather than cardiovascular (CV) events, as the principal outcome in AF patients. A previous large cohort study suggested that AF is not strongly associated with ischemic heart disease26. PubMed, EmBase, and Cochrane Central were searched from inception to June 2016. The following key words and medical terms were used in the literature search: “atrial fibrillation” AND  AND . The search was limited to the English language. The references of included studies were manually screened for potentially eligible studies.The present systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines27. Among the included studies, the “cardiovascular” categories might vary widely. However, studies focusing only on the outcome of SCD, for which ventricular fibrillation was the predominant cause, were not considered. Studies including only AF patients after MI were excluded as well, considering that AF might be complicated by MI, leading to a bias in exploring their association.For inclusion in the meta-analysis, studies had to meet the following criteria: adult patient evaluation; availability of extractable data for MI, CV death, or CV events in individuals with AF. Both retrospective and prospective studies were selected. Studies that enrolled AF patients during the postoperative phase were excluded. The primary outcome of interest was MI, and secondary outcomes included CV death and CV events. The latest American College of Cardiology/American Heart Association guidelines suggested that CV death might be attributed to MI, sudden cardiac death (SCD), heart failure (HF), stroke, cardiovascular procedure, or vascular hemorrhage28. This scoring system mainly incorporated four aspects, including selection, comparability, exposure, and outcomes, with a total score ranging from 0 to 7 points: 0–2 points, low quality; 3–5 points, medium quality; more than 6 points, high quality.Two researchers respectively screened the titles and abstracts, and excluded studies not meeting the inclusion criteria. Potentially eligible full-text articles were subsequently reviewed. In case of disagreement, consensus was achieved through consultation with the corresponding author. The following information was extracted: author, year, study design, region, number of patients, gender, population, AF diagnosis method, proportion of patients with prior MI, CHADS2 score, antithrombotic medications, cardiovascular outcomes, degree of adjustment, and follow-up. Crude and adjusted RRs were both directly extracted or indirectly calculated. The adjustment degree was categorized as “+” for age and/or sex only; “++” for those further adjusting for less than five standard vascular risk factors ; and “+++” for those further adjusting five or more risk factors, including unconventional or socioeconomic factors. The quality of the included studies was appraised by the Newcastle–Ottawa Scale (NOS)29. Heterogeneity was assessed by the I2 statistics30. Publication bias was assessed visually using funnel plots, and statistically by Begg’s and Egger’s tests32. Also, sensitivity analysis was performed by excluding the included studies one by one. A stratified analysis was performed to assess the effects of publication year (2010 or after vs before 2010), study design (prospective cohort vs retrospective cohort), region , sample size (≥10000 vs <10000), mean age (60 years or older vs <60 years), female proportion (≥50% vs <50%), previous MI (≥20% vs <20%), adjustment degree , and follow-up duration (≥5 years vs <5 years). A meta-regression was conducted to investigate the impact of publication year, sample size, mean age, women proportion (%), previous MI (%) and follow-up duration on data heterogeneity. All analyses were conducted using the Stata software . All P values were two sided, with a significance level of 0.05.Relative risk RATIO (RR) with associated 95% confidence interval (CI) was considered the effect estimate for binary outcomes. Hazard ratio was considered to be equivalent to RR in cohort studies. Given the low incidence of MI in AF patients, odds ratios (ORs) could be assumed to be accurate estimates of RRs. Crude and adjusted RRs were pooled separately. When adjusted RRs were presented by multiple multivariate models, the most adjusted one was selected. The meta-analysis was performed using a random-effects modelA total of 733 records from the initial search were identified, including 162 from PubMed, 392 from EmBase, and 179 from Cochrane Central. After discarding 122 duplicates and 505 irrelevant studies, 106 full-text articles were assessed. Further, studies that enrolled single-arm AF patients, included AF patients after ischemic coronary disease, explored the impact of risk factors, or focused on medications/surgeries were excluded. Thirty-two studies were included in a qualitative analysis. Then, two studies of duplicate cohorts and three articles assessing SCD were excluded. The study selection process is displayed in Fig. 56. Table Overall, 27 studies fulfilled the inclusion criteria and were included in the final meta-analysis56. Two studies investigated the same cohort (REACH registry)46, and the one with the largest sample size was selected42. Thus, 10 studies were included in the current meta-analysis. Dries et al. showed two sub-cohorts that were aggregated using fixed- and random-effects models38. Compared with non-AF patients, AF patients had an insignificant trend toward a higher risk of MI , with high heterogeneity  . However, publication year, sample size, mean age, female proportion, and previous MI were not significant contributors of the association between AF and unadjusted MI . AF was significantly associated with a reduction in the risk of MI  . No substantial change in the overall effect was shown after exclusion of any individual study.Adjusted data regarding MI were described in seven studiesP = 0.020). Publication year, sample size, mean age, female proportion, and follow-up duration did not appear to affect meta-regression data  . Sensitivity analysis by excluding any single study did not alter the overall effect. Meta-regression suggested that publication year, sample size, mean age, female proportion, previous MI, and follow-up duration did not account for data heterogeneity (Table P = 0.612) and two European trials (P = 0.224).Ten studies displayed crude data05) Fig. . High hety Table , the res56. The pooled data revealed that AF patients were at a higher risk of CV death compared with non-AF patients  . The meta-regression showed sample size contributed to the association of AF with adjusted MI (P = 0.040). Publication year, mean age, female proportion, previous MI and follow-up duration did not appear to affect meta-regression data . A high heterogeneity was demonstrated   (Table Crude data were shown in eight studies05) Fig. . After s9) Table .Figure 655. Except for one study with an adjustment degree of “++”34, most studies showed a sufficient degree of adjustment (+++). The pooled results demonstrated that AF patients had significantly higher risk of CV events compared with those without AF   Fig. . Sensiti05) Fig. .Figure 7P = 0.86) or Egger’s test (P = 0.40). The funnel plot appeared to be symmetrical  rather than stroke (9.8%) in the contemporary anticoagulated AF population61, which supported the finding that AF is an independent predictor for CV death.Pooled data from adjusted models showed a significant increase by 39% in the risk of MI for AF patients compared with non-AF individuals. This trend was insignificant when pooling crude RRs. It was inferred that potential confounding risk factors for MI might weaken the association of AF with MI. AF patients were associated with markedly increased likelihood of CV death or CV events. The risk of CV death or CV events in patients was approximately twice that in patients without AF . A large long-term cohort showed no significant change in the trend of mortality among AF patients without a preexisting CV disease62. However, participants with other characteristics were not illustrated. Further, Emidin et al. conducted a meta-analysis of cohort studies to evaluate gender-related differences in the associations of AF with CV outcomes, indicating that AF is a stronger risk factor for cardiovascular disease and death in women compared with men, but the impact of confounders was not determined63. Important strengths of this meta-analysis include a comprehensive inclusion of relevant studies with a large sample size. Most cohorts were prospectively designed and population based. Long follow-up was found in most studies with a satisfying response rate. AF occurrence rates were reliably recorded following the International Classification of Diseases code or by direct evidence from electrocardiography (ECG) reports. Further, broad baseline characteristics that ensured the applicability of summary results to worldwide populations were included, representing global data of different regions or races. Both the adjusted and crude data were analyzed, which ensured completeness of the analysis, and demonstrated the potential impact of confounding factors. Overall, adjusted data were consistent in demonstrating the significant association of AF with studied outcomes. Crude data analysis failed to show significance only for MI. Also, data heterogeneity was assessed in multiple ways. No publication bias was found in the present study.A previous study suggested an association of AF with increased risk of mortality in MI patients. New AF with no history of AF before MI remained associated with increased risk of mortality even after adjustment for several important risk factors for AF65. In a porcine model, a rapid atrial pacing could induce ventricular ischemia and endothelial dysfunction in the microvasculature, and increased oxidative stress despite normal coronary vessels showing no atherosclerosis66. In AF patients, myocardial perfusion is impaired, with increased coronary vascular resistance. Notably, these changes are reversible to some extent after cardioversion of sinus rhythm67.Several lines of mechanisms may explain the increased ischemic coronary burden for AF patients. AF could facilitate the induction of ventricular tachyarrhythmia, which is the predominant cause of SCD. This risk was especially high in patients with structural heart disease68. However, Senoo et al. suggested that the risk of cardiovascular death is higher in anticoagulated patients with permanent AF than in those with nonpermanent AF69. A large population-based study revealed that paroxysmal AF does not differ from other types of AFs in risk of overall mortality. In the adjustment model including concurrent MI, stroke, and HF, the risk of CV death is also independent of AF patterns47. Ruigómez et al. revealed that both chronic and paroxysmal AF cases are markedly associated with increased risk of coronary events, without a significant difference between the two subtypes44. A recent large cohort study revealed that AF is significantly associated with increased risk of non–ST-segment-elevation MI (NSTEMI) but not ST-segment-elevation MI (STEMI)3. It was inferred that partial occlusion of coronary arteries or increased oxygen demand, rather than coronary thrombo-embolization, is more likely to explain the observed association of AF with MI3.The impact of various AF patterns on different types of MI remains uncertain. Persistent AF results in worse patient survival compared with paroxysmal AF72. The present findings may be confounded by differences in these measured or unmeasured baseline characteristics, including age, sex, race, hypertension, HF, smoking, and education. It has been demonstrated that black female AF patients, with warfarin prescription, and high CHADS2 score, are associated with higher risk of MI compared with their counterparts51. Of note, the roles of some relevant covariates remain controversial. The risk of acute myocardial infarction was shown to be higher in men with AF than in female counterparts49. However, the meta-analysis proved that AF was a stronger risk factor for CV events and death in women than in men63. With respect to antithrombotic therapy, different anticoagulation combinations, drug types, and treatment compliance are all possible confounding variables for CV outcomes. Some authors recommended adding antiplatelet drugs to vitamin K antagonist (VKA) when AF is complicated with coronary diseases. However, a national cohort revealed that addition of antiplatelet drugs to VKA therapy is not associated with decreased risk of coronary events in AF patients with coexisting coronary heart disease, HF, or vascular disease74. The percentage of patients on antithrombotic therapy was low or unknown in the included cohorts. It is possible that many patients did not undergo standard anticoagulation following the guidelines52. Good anticoagulation was shown to be associated with a significant reduction in major cardiovascular events among AF patients75. Interestingly, a national cohort study suggested that future events tend to mirror the recent disease status in AF patients. For example, patients with previous MI have a higher risk of MI76. However, comorbid conditions were often not coded uniformly or described sufficiently among most cohorts.Although adjusted data analysis showed significant results, various clinical or social factors might independently contribute to the development of ischemic coronary disease in AF patients, which deserves in-depth exploration42. Indeed, as an elusive arrhythmia, AF is difficult to ascertain in population-based cohorts. Data assessing the use of antithrombotic agents, AF type , and CHADS2 score were not collected in several large population-based cohorts36. Meanwhile, inherent recall bias and selection bias were associated with retrospective cohorts49. Most studies did not collect information on continuous ECG recordings49. The information on percentage or indication for antithrombotic therapy could not be obtained in most cohorts. The majority of cohorts enrolled AF patients from individuals with heart disease or stroke39, rather than healthy community-based enrollment, which might have limited the generalization of the current association with all AF populations. For CV death or events, categories may be heterogeneous among studies. Some studies may include stroke in these compound outcomes, which may exaggerate the association of AF with ischemic cardiac outcomes. Besides, the ascertainment of the cause of death may be liable to bias and misclassification77.Several limitations of this meta-analysis should be mentioned. Some studies identified AF patients by medical records rather than via ECG, and might have underestimated the number of undetected patients with asymptomatic AF at baselineIn summary, AF was associated with MI, CV mortality, and CV events. The present study strongly supports the routine surveillance of ischemic heart disease, especially MI, among patients with AF. Future studies are warranted to clarify the interaction among confounding risk factors, and investigate effective preventive measures against adverse outcomes.Supplementary Tables S1-S3


Vitamin D has been linked with improved cancer outcome. This systematic review and meta-analysis investigates the relationship between cancer outcomes and both vitamin D-related genetic variation and circulating 25-hydroxyvitamin D (25OHD) concentration.A systematic review and meta-analysis of papers until November 2016 on PubMed, EMBASE and Web of Science pertaining to association between circulating vitamin D level, functionally relevant vitamin D receptor genetic variants and variants within vitamin D pathway genes and cancer survival or disease progression was performed.A total of 44 165 cases from 64 studies were included in meta-analyses. Higher 25OHD was associated with better overall survival  and progression-free survival . The rs1544410 (BsmI) variant was associated with overall survival  and rs7975232 (ApaI) with progression-free survival . The rs2228570 (FokI) variant was associated with overall survival in lung cancer patients , with a suggestive association across all cancers .Higher 25OHD concentration is associated with better cancer outcome, and the observed association of functional variants in vitamin D pathway genes with outcome supports a causal link. This analysis provides powerful background rationale to instigate clinical trials to investigate the potential beneficial effect of vitamin D in the context of stratification by genotype. The importance of vitamin D for bone health is well established, but the role of vitamin D beyond the skeletal system has been under debate for decades (2D), as a hormone. It has been previously recognised that mutations in genes involved in response to hormones, their metabolism or actions may affect the prognosis of disease and thus act as modifiers. Correspondingly, 1,25(OH)2D binds to the VDR (a ligand-dependent transcription factor) and polymorphisms in the VDR gene have been shown to modify the activity of this VitD–VDR complex , as a pre-hormone and the primary active form, 1,25-dihydroxyvitamin D Three aspects further strengthen the case for understanding the associations between vitamin D and cancer outcomes: first, cancer incidence and mortality are increasing ; second,Here we present a systematic review and meta-analysis examining the role of vitamin D on cancer progression and survival. We conducted a comprehensive evaluation of the literature that examines the associations between cancer outcomes and genetic factors involved in the vitamin D pathway, in addition to circulating 25OHD concentration. Focus on vitamin D-related genetic variation allowed us to partially mitigate against potential confounding or reverse causation, biases that typically limit implications of findings from observational vitamin D studies.VDR, rs1544410, BsmI, rs10735810, rs2228570, FokI, rs7975232, ApaI, rs11568820, Cdx-2, rs2282679, rs12785878, rs10741657 and rs6013897. Finally, we also included variation in genes related to vitamin D synthesis, transport or metabolism: 1-α-hydroxylase, CYP27B1, 25-hydroxylase, CYP2R1, 24-hydroxylase, CYP24A1, vitamin D binding protein, 27-hydroxlyase and CYP27A1. Genetic variants beyond those explicitly searched for were only included if previously shown to affect vitamin D metabolism. We considered all human research full text articles, with no restriction on language or article type. Bibliographies of retrieved papers and previous reviews were hand-searched to identify other relevant studies.We performed a systematic literature review and meta-analysis following PRISMA guidelines , EMBASE Study inclusion ‘PICO' criteria were as follows: (i) participants: individuals of any age who received a diagnosis of cancer; (ii) intervention/Exposures: assessment of vitamin D status or genetic factors known to affect vitamin D concentration, metabolism or pathways; (iii) comparators: study reports a quantitative association between cancer outcome and either vitamin D status  sampled at most 1 year prior to the diagnosis, or any germline genetic variation or gene expression in normal tissue; and (iv) Outcome: cancer-specific or all-cause mortality, or disease progression . Observational retrospective and prospective cohorts were included.In relation to patients, exclusion criteria were: (i) pre-cancerous lesions, and (ii) mixed-cancer cohort without site-specific reporting; in relation to exposures: (iii) vitamin D intake and supplementation, (iv) acquired non-germline mutations or tumour gene expression, and (v) predicted vitamin D status; in relation to outcomes: (vi) prognostic markers such as Prostate Specific Antigen or Breslow thickness, (vii) population cancer mortality rates; in relation to study/publication type: (viii) ecological studies, and (ix) reviews, editorials, case reports, conference abstracts and nonclinical publications. If the same patient cohort was reported on more than once, we used the highest quality, largest sample size or most recent publication. Article titles and abstracts were screened for eligibility, independently by two authors (PVS and LZ or FOS). Disagreements were resolved by discussion and review of full text.The data extraction was performed by a single investigator (PVS or FOS) using the predefined data fields and extraction was cross-checked by a second investigator in its entirety (FOS or PVS). The data from eligible studies were extracted using a tailored data extraction form that included the following information: first author, publication year, location or ethnicity of patients, sample size, mean age, gender, cancer site (subtype/histology where relevant), cancer stage, any interventions , vitamin D exposure studied and important meta-data , covariates considered, details of outcomes studied, and follow-up time. Finally, hazard ratios (HR) and 95% confidence intervals (95% CIs) adjusted for the maximum number of confounding variables were extracted. We preferentially focused on cancer-specific mortality, but if these data were not available, all-cause mortality was used instead. Relative risk estimates (RR) or adjusted odds ratios (OR) were extracted where HR were not given and used in meta-analysis . Study aThe methodological quality of all studies included in the systematic review was performed using the Newcastle-Ottawa Quality Assessment Scale . The genome browser ENSEMBL (80 GRCh38.p2) was used to determine if alias names existed . HR values were inverted where needed, so that the same allele acted as the reference. Where additive models were used, the HR values were squared in order to approximate the HR value for comparison between two homozygotes.For SNPs, the rs number naming convention was typically used in the paper and some recoding was needed to ensure that uniform reference system was followed. For example, where a restriction fragment length polymorphism was referenced, the mutation and risk allele were recoded  were used to calculate weighting for each study. The DerSimonian and Laird random-effects model was used to calculate pooled HR because of the med in R , and themed in R . P-valueI2 statistic was calculated to quantify the degree of heterogeneity between studies and assess impact on the meta-analysis (−1), and (vii) the degree of deficiency in ‘low' category (mean/median 25OHD concentration below or ⩾12.5 ng ml−1). Publication and selection bias was investigated by checking for asymmetry in the funnel plots and running the Egger's regression test  after exclusion of studies at high risk of bias, (ii) limited to studies at low risk of bias only, (iii) limited to studies that looked at cancer-specific mortality, (iv) excluding studies that used 25OHD as a continuous variable, and (v) excluding studies that reported RR or OR. The analysis  accordinion test .N=2708) or abstracts (N=262). One hundred full-texts were considered for inclusion and assessed for eligibility and 19 were excluded. Finally, 81 articles were kept for the systematic review and 64 of these were included in the meta-analysis. The main characteristics of included studies are summarised in A flowchart illustrating study selection is shown in N=24) and Europe; breast cancer was most commonly studied (N=15), followed by nine studies (each) on prostate cancer and colorectal cancer. In total, 157 HR estimates for a range of exposure-outcome pairs were included in meta-analyses: 77 estimates (from 41 studies) for association with 25OHD, and 80 estimates (from 27 studies) relating to genetic factors. Separate estimates were extracted for different patient subgroups  in the ‘low' category in another study  had a low risk of bias, 35 (43%) had an uncertain, and 11 (14%) had a high risk of bias. The risk of bias assessment summary per each domain is shown in −1; , or when stratifying by the lower category mean/median below or greater than 12.5 ng ml−1  .Forty-eight estimates from 38 studies were included in the meta-analysis of 25OHD and survival (17 studies (45%) examined cancer-specific mortality), comprising in total 24 013 cancer patients. Twelve cancer types were represented: breast, haematological, head and neck, colorectal, lung, prostate, skin, pancreatic liver, gastric, kidney and ovarian cancers. Overall, a significantly reduced risk of death was observed when comparing those with high to those with low vitamin D levels; meta-analysis HR=0.74, 95% CI=0.66 to 0.82 . The sam−1; , or when stratifying by the lower category mean/median below or greater than 12.5 ng ml−1  , rs1544410 (BsmI), rs731236 (TaqI), rs11568820 (Cdx2), and rs7975232 (ApaI). In meta-analysis, rs1544410 TT/TC genotypes were associated with worse survival compared to CC genotype  and a consistent albeit non-significant association was found across all cancers . A significant association was observed with rs731236 (Taq1) variant when limited to studies at low risk of bias  examined cancer-specific mortality. By far, the most commonly studied were polymorphisms in rs7975232 AA carriers had significantly worse survival than CC carriers . Additionally, a suggestive association was observed for vitamin D binding protein variant rs2282679  in meta-analysis of two studies.Ten studies examined the effect of genetic variation on disease progression . In metaThere was some evidence of heterogeneity between studies in meta-analysis of 25OHD and some evidence of publication bias . A non-iTaqI-FokI, TTFf/TtFf) haplotype was significantly associated with reduced overall survival  (AA) genotype in prostate cancer . However, evidence that genetic factors linked to vitamin D metabolism and pathways impact upon cancer survival may be used to counter such concerns and support a causal link. In our meta-analysis, we found evidence of an association between the 2D and hence its downstream effects VDR or vitamin D pathway genetic variants and cancer outcomes, and no meta-analyses have been published to date. A review by Kostner et al (VDR polymorphisms and cancer prognosis are strongest for prostate cancer (rs2228570), breast cancer  malignant melanoma (rs1544410), and renal cell carcinoma (rs731236) but did not perform meta-analysis on these data.Few studies to date have analysed the associations between et al ((DHCR7 and CYP2R1) were associated with both all-cause and cancer mortality, supporting a causal role of vitamin D. To date, there are no published findings from randomised controlled trials (RCT) assessing the effect of vitamin D supplementation Interestingly, Afzal −1 is greater than effect per 5 ng ml−1 increase. Therefore, there is a need for a consensus in category definition and reporting of effect sizes: future original studies should report effect sizes using internationally agreed cutoffs, such as those given by the Institute of Medicine, solely or in addition to study-specific cutoff values chosen. Generally, variability in exposure categories results in a more heterogeneous estimates and is likely to increase statistical uncertainty and hence bias results towards the null. Nonetheless, our summary findings remain largely unchanged when the analysis was limited according to the difference in 25OHD between the compared groups.A major issue that is typically taken poor notice of in vitamin D meta-analyses—namely, a very large variability in vitamin D category definition amongst studies, is for the first time being highlighted and transparently shown in our review. Vitamin D categories differed in level as well as range—as a result, large heterogeneity in exposure definition occurred and study point-estimates are difficult to compare: it is, for example, unsurprising that the reported effect per 20 ng mlThere are some additional limitations of the present work. First, a number of relevant studies were published after the time limits stipulated in our search strategy and so are not included in our meta-analysis. Some such papers support the conclusions presented here  knockout mice (In the present study, results for all cancers combined are given, in addition to site-specific findings, we yet fully acknowledge that cancer is a heterogeneous disease. However, numerous studies have shown involvement of vitamin D on key hallmarks of cancer, many of which are common to all cancers; preclinical studies demonstrate effects on cell cycle arrest, cell adhesion, differentiation, proliferation, tumour angiogenesis, and apoptosis in human cancer cell lines (Next, in reporting the impact of genetic variation on outcome, we acknowledge that ethnic differences in VDR variation exist, which might interfere with the findings from genetic studies, as ethnicity is directly linked to the skin type and vitamin D synthesis. Meanwhile, VDR variants may interact with circulating 25OHD to impact outcome, yet only a small number of studies examined these putative gene–environment interactions. Finally, we observed some evidence of heterogeneity and publication bias overall; however, findings from sensitivity analysis were highly consistent and supportive of main findings.Despite these limitations, the present work includes a novel meta-analysis, investigating the association between vitamin D-related genetic variation and cancer outcome, in addition to a ∼50% larger meta-analysis of circulating 25OHD and cancer outcome compared to a previous review (In conclusion, the consistent evidence across the studies presented in the current review demonstrates a clear and strong association between low baseline vitamin D levels and poorer cancer survival. The associations between vitamin D-related genetic variants and cancer survival support an interpretation that vitamin D may play an important role in influencing cancer outcome. However, a causal link cannot be conclusively established from observational studies; hence, well-designed and adequately powered RCTs are needed to evaluate the clinical application of vitamin D in augmenting standard follow-up and adjuvant chemotherapy regimens. Understanding the mechanism of action of genetic factors promises to provide further insight into biological determinants of response to treatment and could help inform prognosis.


Environmental risk assessment (ERA) of genetically modified (GM) crops is a process to evaluate whether the biotechnology trait(s) in a GM crop may result in increased pest potential or harm to the environment. In this analysis, two GM insect-resistant (IR) herbicide-tolerant maize hybrids (MON-89Ø34-3 × MON-88Ø17-3 and MON-89Ø34-3 × MON-ØØ6Ø3-6) and one herbicide-tolerant GM hybrid (MON-ØØ6Ø3-6) were compared with conventional maize hybrids of similar genetic backgrounds. Two sets of studies, Experimental Phase and Pilot Phase, were conducted across five ecological regions (ecoregions) in Mexico during 2009–2013, and data were subject to meta-analysis. Results from the Experimental Phase studies, which were used for ERA, indicated that the three GM hybrids were not different from conventional maize for early stand count, days-to-silking, days-to-anthesis, root lodging, stalk lodging, or final stand count. Statistically significant differences were observed for seedling vigor, ear height, plant height, grain moisture, and grain yield, particularly in the IR hybrids; however, none of these phenotypic differences are expected to contribute to a biological or ecological change that would result in an increased pest potential or ecological risk when cultivating these GM hybrids. Overall, results from the Experimental Phase studies are consistent with those from other world regions, confirming that there are no additional risks compared to conventional maize. Results from Pilot Phase studies indicated that, compared to conventional maize hybrids, no differences were detected for the agronomic and phenotypic characteristics measured on the three GM maize hybrids, with the exception of grain moisture and grain yield in the IR hybrids. Since MON-89Ø34-3 × MON-88Ø17-3 and MON-89Ø34-3 × MON-ØØ6Ø3-6 confer resistance to target insect pests, they are an alternative for farmers in Mexico to protect the crop from insect damage. Additionally, the herbicide tolerance conferred by all three GM hybrids enables more cost-effective weed management.The online version of this article (doi:10.1007/s11248-016-9991-z) contains supplementary material, which is available to authorized users. Mexico’s regulatory framework addresses the cultivation of genetically modified (GM) crops , corn earworm (Helicoverpa zea Boddie), and cutworms (Agrotis ipsilon Hufnagel) , MON-89Ø34-3 × MON-ØØ6Ø3-6 (two stacked IR traits plus a single HT trait), and MON-ØØ6Ø3-6 (single HT trait)—grown at several sites in Mexico for evidence of biologically meaningful agronomic and phenotypic differences or adverse ecological effects due to the introgression of IR and/or HT biotech traits (ERA). The second objective was to confirm biological efficacy in terms of plant response of MON-89Ø34-3 × MON-88Ø17-3 and MON-89Ø34-3 × MON-ØØ6Ø3-6 maize hybrids against lepidopteran and coleopteran insect pests, and to assess tolerance to glyphosate-based herbicides and efficacy of weed management programs by all three maize hybrids.Study sites in maize production areas were located within five ecoregions: (i) 9.5.1.2 = Tamaulipas coastal plain with xerophile vegetation or without apparent vegetation; (ii) 10.2.2.8 = floodplains of the Yaqui, Mayo, and Fuerte Rivers with xerophile shrubs and mesquite; (iii) 10.2.3.3 = floodplains and rolling hills of the Vizcaíno and Magdalena Deserts with xerophile sarco-sarcocrassicaule and halophytic vegetation; (iv) 10.2.4.1 = central plains of the Chihuahuan Desert with xerophile-halophytic microphyllus vegetation; and (v) 14.3.1.2 = Sinaloa coastal plain with low thorny forest  that confer resistance against aboveground lepidopteran insect pests and belowground local Diabrotica species. It also expresses the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) protein, which confers tolerance to glyphosate herbicide. GM hybrid MON-89Ø34-3 × MON-ØØ6Ø3-6 expresses two Bt proteins (Cry1A.105 and Cry2Ab2) that confer resistance against aboveground lepidopteran insects pests, and also expresses the EPSPS protein. GM hybrid MON-ØØ6Ø3-6 expresses only the EPSPS protein.The test materials were GM maize hybrids MON-89Ø34-3 × MON-88Ø17-3, MON-89Ø34-3 × MON-ØØ6Ø3-6, and MON-ØØ6Ø3-6, and the control materials were corresponding conventional (non-GM) isohybrids. Within each study, the three GM maize hybrids and the conventional maize control hybrid were all in the same hybrid (genetic background). At all but one site (Chihuahua), the hybrids were in a genetic background broadly adapted to the environmental conditions of northern Mexican states; at Chihuahua, an early-maturing hybrid background was used. GM hybrid MON-89Ø34-3 × MON-88Ø17-3 expresses three 2, and Pilot Phase plot size ranged from 398.7 to 4128 m2 (Supplementary Table 2). The main soil textures varied across locations and included clay, silty clay, clay loam, sandy loam, sandy clay loam, and sandy silt. Row spacing varied from 0.65 to 0.92 m, with a seeding rate of 5 to 10 seeds per meter and seed planting depth of 2 to 9 cm. Plot management was according to the recommendations by INIFAP-CIRNO for maize , a glyphosate-containing herbicide, were made on the three GM hybrids at rates of 2 to 4 L ha−1. Weed control for the conventional control was mechanical  and/or by applications of selective herbicides. Subsequently, weed control was evaluated at approximately 11, 20, and 30 days after herbicide treatment in all of the studies.Experimental Phase plot size ranged from 12 to 384 mDiabrotica root damage, corn earworm damage, and Spodoptera leaf damage) were evaluated according to standard methods  seedling damage was also documented (Supplementary Table 3). Weed control levels  by total applications of glyphosate vs. mechanical weed control treatments were documented at multiple locations. Agronomic, phenotypic, and insect damage data collected from each individual study were subject to an analysis of variance (ANOVA). The means, standard errors, and sample sizes of the test and control hybrids for agronomic, phenotypic, and insect damage measurements from each study were generated from the statistical analyses of individual studies and included in a meta-analysis.GM maize hybrids MON-89Ø34-3 × MON-88Ø17-3, MON-89Ø34-3 × MON-ØØ6Ø3-6, and MON-ØØ6Ø3-6 and a corresponding conventional isohybrid control were planted in each of 36 studies  in a randomized complete block design (RCBD) with three to four replications and up to four locations per ecoregion per year (Supplementary Tables 1 and 2). Twelve agronomic and phenotypic characteristics were evaluated throughout the season (Supplementary Table 3). In addition, plant response to target insect pests . Separate meta-analyses were conducted for each of the three test materials within each of the two regulatory phases  using random-effects models ; if the interval does not contain zero and is negative, then the standardized difference favors the control (test minus control is negative). Statistical significance is defined by a p value <0.05. If the p value is less than 0.05, then the combined study effect is significantly different from zero, which means that the test and control are significantly different.A meta-analysis uses standardized differences, i.e.,p in Eq. . A randoIn addition, a regression analysis was implemented on yield data from IR hybrids MON-89Ø34-3 × MON-88Ø17-3 and MON-89Ø34-3 × MON-ØØ6Ø3-6 relative to the conventional control across all studies for which data were available. This analysis included sites that could not be included in the meta-analysis due to fewer than three replicates of data for traits analyzed. The numbers of studies included in the regression analysis were 32 Experimental Phase and 26 Pilot Phase studies.Field evaluations of MON-89Ø34-3 × MON-88Ø17-3, MON-89Ø34-3 × MON-ØØ6Ø3-6, and MON-ØØ6Ø3-6 were well distributed and representative of each of the five ecoregions during 2009–2013 Fig. , which ip ≤ 0.05) between MON-89Ø34-3 × MON-88Ø17-3 and the conventional hybrid control were found for ear height (108.2 vs. 103.3 cm), plant height (210.2 vs. 204.0 cm), grain moisture (18.8 % vs. 18.0 %), and grain yield (10.2 vs. 9.2 t ha−1). Statistically significant differences between MON-89Ø34-3 × MON-ØØ6Ø3-6 and the conventional hybrid control were detected for seedling vigor , plant height (208.2 vs. 201.7 cm), grain moisture (18.5 % vs. 18.1 %), and grain yield (10.0 vs. 9.1 t ha−1). The only statistically significant difference detected between MON-ØØ6Ø3-6 and the conventional control was seedling vigor (7.2 vs. 6.5). For MON-89Ø34-3 × MON-88Ø17-3 and MON-89Ø34-3 × MON-ØØ6Ø3-6 GM maize hybrids, which expressed both insect control (IR) and HT traits, plant height, grain moisture, and grain yield were the three characteristics in common that showed significantly higher values than the conventional hybrid control.The results of the meta-analysis for the agronomic and phenotypic characteristics for Experimental Phase studies are presented in Fig. p ≤ 0.05) were detected for grain yield  and grain moisture . The mean values for grain moisture and grain yield were higher for the GM maize hybrids in all comparisons  between MON-89Ø34-3 × MON-88Ø17-3 and the conventional control for Diabrotica root damage (0.05 vs. 0.11 rating), corn earworm damage (0.46 vs. 2.40 cm2), and Spodoptera leaf damage (0.20 vs. 1.94 rating) (Table 2) and Spodoptera leaf damage (0.33 vs. 2.23 rating)  for stalk borer tunnel length (0.02 vs. 0.18 cm), stalk borer tunnel number (0.00 vs. 0.04), Diabrotica root damage (0.01 vs. 0.02 rating), corn earworm damage (0.19 vs. 2.08 cm2), Spodoptera leaf damage (0.06 vs. 1.49 rating) and cutworm (Agrotis and/or Spodoptera spp.) damage (0.00 vs. 35.88 seedlings) (Table p ≤ 0.05) for corn earworm damage (0.11 vs. 1.91 cm2) and cutworm (Agrotis and/or Spodoptera spp.) damage (0.00 vs. 37.11 seedlings)  and Pilot Phase (2012–2013) studies. The weed inventories included species adapted to the different regions and are typical of agricultural fields  in North America , better plant health, and overall less stressful conditions for the GM hybrids, enabling them to reach more of their full yield potential.Meta-analysis of agronomic and phenotypic characteristics from up to 15 Experimental Phase studies  were detected for grain yield and grain moisture  control, which was obtained using best regional management practices across the Experimental and Pilot studies, could represent a substantial increase in maize production in the northern states of Mexico.Similarly, analysis from up to 23 Pilot Phase studies  and Spodoptera frugiperda , and was estimated at US$170 M for the period 1998–2003  to apply an insect-control treatment was reached once or twice during the growing season for MON-ØØ6Ø3-6 and the conventional isohybrid controls. These observations are consistent with those by Finger et al. (Spodoptera spp.) would help reduce the amount of insecticide active ingredients used per year in Mexico and would result in production cost savings for growers. In addition, use of GM IR hybrids may provide benefits associated with the reduction of pesticide loads in the environment.The threshold level (5 % plants damaged) to trigger lepidopteran pest control applications was never reached for the MON-89Ø34-3 × MON-88Ø17-3 and MON-89Ø34-3 × MON-ØØ6Ø3-6 GM maize hybrids in any study. This was expected given the intrinsic lepidopteran and coleopteran IR traits in these two hybrids conferred by the expression of r et al. , Areal er et al. , and Blar et al. , thus coThese desirable outcomes from adopting GM IR crops have already been achieved by GM cotton growers in Mexico . The main soil textures found across locations were clay, silty clay, clay loam, sandy loam, sandy clay loam, and sandy silt, with climates ranging from semi-warm , to warm . Rainfall was more variable, but most ecoregions received less than 200 mm with the exception of ecoregion 9.5.1.2 (Tamaulipas), with annual rainfall of 1069 mm. Likewise, the altitude was less than 400 m above sea level for most of the regions. However, ecoregion 10.2.4.1 (Chihuahua) had an altitude that ranged from 1000 to 2400 m above sea level. As previously mentioned, however, even geographically distinct ecoregions show homogeneity in factors such climate, soils, and water availability that define geographic zones within these ecoregions that are well suited for agricultural production and are used for this purpose. The similarity in agroclimatic characteristics of the agricultural sites where CFTs were implemented (Supplementary Table 1), in addition to the consistent results observed across all 36 studies through the use of standardized protocols, measurement endpoints, and data recording methods Tables . FurtherThe Mexican regulatory framework requires an ERA to be submitted with each application for a CFT of a GM crop product and requires the implementation of plant characterization studies to test risk hypotheses on a case-by-case approach. To improve efficiency in the field testing efforts, representative and strategic field locations with similar agroecological characteristics across ecoregions are recommended to obtain results that would be transportable from one ecoregion to another Below is the link to the electronic supplementary material.


TNF-α) rs1800629 and rs361525 polymorphisms on sepsis risk. We found that TNF-α rs1800629 was associated with increased sepsis risk in the overall population in four genetic models, including A vs. G =1.32), GA vs. GG , GA+AA vs. GG , and carrier A vs. carrier G . Subgroup analyses showed a similar result for Asian patients . TNF-α rs361525 was also associated with increased sepsis risk in Asian patients in the four genetic models . Begg’s and Egger’s tests excluded large publication bias, and sensitivity analysis indicated stable results. Our results suggest that the G/A genotype of TNF-α rs1800629 and rs361525 increases sepsis risk in an Asian population.This meta-analysis of 23 eligible articles comprehensively and quantitatively evaluated the effects of tumor necrosis factor-α ( TLR4 (toll like receptor 4) SNPs, rs4986790 and rs4986791  rs1799768 polymorphism , ethnicity (Caucasian or Asian), and sepsis severity .We used the Mantel-Haenszel test to determine P>0.05 in both tests would exclude a large publication bias. We also performed a sensitivity analysis to evaluate the robustness of our data. All analyses were performed using Stata/SE 12.0 software .We evaluated publication bias using both Begg’s test and Egger’s test.


Diabetic retinopathy (DR), the primary retinal vascular complication of diabetes mellitus (DM), is a leading cause of vision impairment and blindness in working-age population globally. Despite mounting concerns about the emergence of DM as a major public health problem in the largest developing country, China, much remains to be understood about the epidemiology of DR. We aimed to investigate the prevalence of and risk factors for DR, and estimate the burden of DR in China in 2010.China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedicine Literature Database (CBM-SinoMed), PubMed, Embase and Medline were searched for studies that reported the prevalence of and risk factors for DR in Chinese population between 1990 and 2017. A random-effects meta-analysis model was adopted to pool the overall prevalence of DR. Variations in the prevalence of DR in different age groups, DM duration groups and settings were assessed by subgroup meta-analysis and meta-regression. Odds ratios (ORs) of major risk factors were pooled using random-effects meta-analysis. The number of people with DR in 2010 was estimated by multiplying the age-specific prevalence of DR in people with DM with the corresponding number of people with DM in China. Finally, the national number of people with DR was distributed into six geographic regions using a risk factor-based model.A total of 31 studies provided information on the prevalence of DR and 21 explored potential risk factors for DR. The pooled prevalence of any DR, nonproliferative DR (NPDR) and proliferative DR (PDR) was 1.14% (95% CI = 0.80-1.52), 0.90% (95% CI = 0.56-1.31) and 0.07% (95% CI = 0.02-0.14) in general population; In people with DM, the pooled prevalence rates were 18.45% (95% CI = 14.77-22.43), 15.06% (95% CI = 11.59-18.88) and 0.99% (95% CI = 0.40-1.80) for any DR, NPDR and PDR, respectively. The prevalence of any DR in DM patients peaked between 60 and 69 years of age, and increased steeply with the duration of DM. DM patients residing in rural China were at a higher risk to have DR than those in urban areas. In addition, insulin treatment, elevated FBG level and higher HbA1c concentration were confirmed to be associated with a higher prevalence of DR in people with DM, with meta-ORs of 1.99 (95% CI = 1.34-2.95), 1.33 (95% CI = 1.12-1.59) and 1.15 (95% CI = 1.09-1.20) respectively. In 2010, a total of 13.16 million (95% CI = 8.95-18.00) Chinese aged 45 years and above were living with DR, among whom the most were in South Central China and the least were in Northwest China.DR has become a serious public health problem in China. Optimal screening of and interventions on DR should be implemented. Improved epidemiological studies on DR are still required. Diabetic retinopathy (DR), the primary retinal vascular complication of diabetes mellitus (DM), is a leading cause of vision impairment and blindness in the working-age population -4. In thAlthough available diagnostic and therapeutic advancements, such as optimum management of DM and early detection of DR, can substantially reduce the risk of visual deterioration, DR remains an important cause of visual impairment and blindness globally -16. In 2Despite mounting concerns about the emergence of DM as a major public health problem in the largest developing country, China, epidemiological data on DR in Chinese population are still rather scarce or inconsistent ,21-23. TTo fill the gaps outlined above, we conducted a comprehensive systematic review, in both Chinese and English databases, to retrieve studies that reported the epidemiology of DR in China from 1990 onwards. Based on the existing evidence, we aimed to: (1) pool the overall prevalence of DR in both general Chinese population and people with DM; (2) estimate the effects of demographic and geographic variables on the prevalence of DR in people with DM; (3) assess the major risk factors for DR in people with DM; and (4) quantify the national and subnational burden of DR in 2010.This systematic review and meta-analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement ,27.Online Supplementary Document(Online Supplementary Document). To supplement the electronic database search, reference lists of eligible publications and related reviews were also scanned to identify other potentially pertinent studies. The literature search was limited to studies published between January 1990 and December 2017. No language restrictions were imposed on searches or search results.Three Chinese and three English electronic bibliographic databases, namely China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedicine Literature Database (CBM-SinoMed), PubMed, Embase, and Medline, were searched to locate all relevant publications that reported the epidemiology of DR in China. Our comprehensive search strategies combined terms of diabetic retinopathy, epidemiology  and China  using both controlled vocabularies  and free text words. Search queries were optimised to fit the specific features of each database, and the full search strategies are detailed in Table S1 in To be included in the systematic review and meta-analysis, studies had to be population-based and reported the prevalence of DR or risk factors for DR. Depending on how the study population was sought, the identified population-based studies can be classified into three categories: community-based, primary health care management (PHCM)-based and registry-based. Community-based studies derived their study sample from the general population , whereas PHCM-based and registry-based studies derived their study sample from all the primary care settings or primary care systems in a defined geographical area. Thus, both PHCM-based and registry-based studies attempted to capture all, or at least a random sample, of people with DM in a defined geographical area. For the purpose of pooling prevalence rates of DR, the included studies must be community-based, and of particular note, include both newly detected and physician-diagnosed DM cases simultaneously (to avoid overestimation); To assess the risk factors for DR in people with DM, the included studies could be community-based, PHCM-based or registry-based, where DM cases could be either newly detected or physician-diagnosed, or both. To avoid suspected bias inherent to univariate analysis, the estimation of odds ratios (ORs) in studies that reported the risk factors for DR must be based on a multivariate study design.Studies that were conducted in the T1DM group were excluded, whereas those focused on people with T2DM were retained. Studies that contained both T1DM and T2DM cases were not excluded if the proportion of people with T1DM was small (<10%). For studies where the type of DM was not specified but all other criteria were fulfilled, it was assumed that those studies contained both T2DM cases and a small proportion of T1DM cases. Otherwise, the type of DM could be speculated by the age at diagnosis of DM (if available), where people diagnosed before 30 years were deemed as with T1DM and those after 30 years were T2DM . To be eAfter deleting duplicate records within and between different bibliographic databases, the remaining titles and abstracts were independently reviewed by two authors (PS and JY) to identify potentially eligible articles that required a full appraisal. In cases of multiple publications from the same study or overlapping data, preference was given to the most recent one or the one with the most inclusive information. Consensus was achieved for any discrepancies in study eligibility through discussion. With a predefined data-collection form, the following information was extracted from the included studies, where possible:Characteristics of the study: author(s), publication year, study year, study type , sampling method, study design , study setting  and location, geographic region, DR assessment method and grading system;Characteristics of the sample : number of the sample, age , gender , DM definition, DM classification , and duration of DM;Prevalence data: the number of people with DR and the number of participants who had been tested for DR, by age, DM duration, gender, setting and DR subtype;Risk factor data: definition of risk factor, OR and corresponding confidence intervals (CIs).According to the definitions from National Bureau of Statistics of China, the geographic regions where the studies were carried out were classified into six categories: East China, North China, Northeast China, Northwest China, South Central China, and Southwest China  [I2 values of less than 25% corresponded to mild heterogeneity, of from 25% to 50% reflected moderate heterogeneity, and of greater than 50% represented high heterogeneity, respectively [The crude prevalence of DR was first computed for each study and then double-arcsine transformed by using the Freeman-Tukey method -33. Hete chance) ,35. A p-ectively -36. Becaectively ,36. For ectively . Publicaectively -40. The For the prevalence of any DR in people with DM, potential sources of heterogeneity were investigated using subgroup meta-analysis and meta-regression. In subgroup meta-analysis, the prevalence of any DR was estimated for different age groups and DM duration groups. This was done because age- and DM duration-specific prevalence of any DR in people with DM was universally provided by the included studies. Moreover, the individual associations between prevalence of any DR and study-level variables were evaluated by univariable meta-regression using unrestricted maximum likelihood method. The prespecified variables included gender , setting , geographic region and study year. Because only a few variables were individually significant, a multivariable meta-regression was not subsequently performed.To investigate the risk factors for any DR in people with DM, a random-effects meta-analysis was employed a priori because of anticipated variation in study populations, geography and study design. As a rule, we only included risk factors that were investigated in at least three studies using multivariate design, and the definitions of the same risk factor should be similar across all included studies. Finally, 11 factors  met our criteria and were included in meta-analysis.Online Supplementary Document(Online Supplementary Document) [At the final stage, the national number of cases with any DR (“any DR envelope”) was estimated by multiplying the age-specific prevalence of any DR in people with DM with the corresponding number of people with DM in China. For this purpose, the 2011 national baseline survey of China Health and Retirement Longitudinal Study (CHARLS), a nationally representative survey of Chinese people aged 45 years and older by using a four-stage, stratified, cluster sampling procedure, was selected to provide prevalence estimates of DM in China for the year 2010, and the Chinese population data were obtained from the United Nations Population Division (UNPD) . The numocument) ,43. Thenocument) ,45. Fourwww.gadm.org).A two-sided p-value of less than 0.05 indicated statistical significance except for the Q statistics, in which a significance level of less than 0.1 was specified. All statistical analyses were done with R version 3.3.0  and STATA version 14.0 . All maps were drawn by ArcMap version 10.1  using the China base map obtained from the Global Administrative Areas (GADM) database .The initial search strategy yielded 9982 records. After removal of 4644 duplicates, a total of 5338 records were reviewed for relevance by titles and abstracts, of which 1147 were assessed in full-text form. Finally, 41 articles met eligibility criteria and were included in the systematic review. Of these, 31 studies provided information on the prevalence of DR and 21 explored potential risk factors for DR. The process of study selection is summarised in Online Supplementary Document(Online Supplementary Document) lists the detailed characteristics of every study. For the 31 studies that reported the prevalence of DR and the 21 studies on risk factors for DR, the majority were published after 2010, implying the necessity for an updated analysis of the epidemiology of DR in China. The studies on the prevalence of DR were all community-based investigations, covering all the six geographic regions across China ), the pooled prevalence of any DR in general population varied from 1.08% (95% CI = 0.76-1.46) to 1.19% (95% CI = 0.86-1.58), and that in people with DM ranged from 17.67% (95% CI = 14.12-21.53) to 19.01% (95% CI = 15.38-22.94), no single study significantly influenced the overall pooled prevalence in the meta-analysis. No publication bias was evident based on the visual evaluation of the funnel plot, Egger’s test and Begg’s test ).By using random-effects meta-analysis, the pooled prevalence of any DR in general Chinese population was 1.14% (95% CI = 0.80-1.52), and that in people with DM was 18.45% (95% CI = 14.77-22.43) (Online Supplementary Document(Online Supplementary Document)), where the pooled prevalence of NPDR in general population ranged from 0.79% (95% CI = 0.49-1.14) to 0.99% (95% CI = 0.63-1.42) and that in people with DM from 13.92% (95% CI = 11.20-16.87) to 15.85% (95% CI = 12.48-19.53). Among studies that reported the prevalence of NPDR in general population, potential publication bias was revealed by the asymmetrical shape of funnel plot, Egger’s test and Begg’s test, whereas no publication bias was suggested for studies that reported the prevalence of NPDR in people with DM ).For NPDR, the pooled prevalence in general population was 0.90% (95% CI = 0.56-1.31), and that in people with DM was 15.06% (95% CI = 11.59-18.88) by use of random-effects meta-analysis (Online Supplementary Document(Online Supplementary Document)). For studies that reported the prevalence of PDR in general population, visual inspection of the funnel plot and Begg’s test demonstrated some evidence of significant publication bias, which was not confirmed by the Egger’s test. No publication bias was detected in the meta-analysis of PDR prevalence in people with DM ).As shown in Online Supplementary Document(Online Supplementary Document).The age-specific prevalence of any DR in people with DM was derived based on subgroup meta-analysis (Online Supplementary Document(Online Supplementary Document).By pooling the prevalence of any DR in strata of DM duration group, it was revealed that the prevalence of any DR in people with DM substantially increased with the duration of DM. Four different DM duration groups were used: 0-year (newly detected), 1-4 years, 5-9 years and 10 years and longer. According to the subgroup meta-analysis (According to the univariable meta-regression (Online Supplementary Document(Online Supplementary Document)). Risk factors for any DR were reported in various ways, among which 11 were with consistent definitions and sufficient information, and therefore were included in evidence synthesis (Online Supplementary Document(Online Supplementary Document).A total of 21 studies described the risk factors for any DR in people with DM by multivariate logistic regression (Table S5 in Online Supplementary Document(Online Supplementary Document) for more details). By applying the age-specific prevalence of any DR in people with DM and the corresponding age-specific DM cases, the number of middle-aged and older Chinese with any DR was estimated to be 13.16 million (95% CI = 8.95-18.00) in 2010, translating to an overall prevalence of 3.06% (95% CI = 2.08-4.19) in general middle-aged and older Chinese and of 18.24% (95% CI = 12.41-24.95) in middle-aged and older Chinese with DM  in middle-aged and older Chinese in 2010 , 0.90% (95% CI = 0.56-1.31) and 0.07% (95% CI = 0.02-0.14); In people with DM, the pooled prevalence rates were 18.45% (95% CI = 14.77-22.43), 15.06% (95% CI = 11.59-18.88) and 0.99% (95% CI = 0.40-1.80) for any DR, NPDR and PDR, respectively. The prevalence of any DR in DM patients peaked between 60 and 69 years of age, and increased steeply with the duration of DM. DM patients residing in rural China were at a higher risk to have any DR than those in urban areas. In addition, insulin treatment, elevated FBG level and higher HbA1c concentration were confirmed to be associated with a higher prevalence of any DR in people with DM. In 2010, a total of 13.16 million (95% CI = 8.95-18.00) Chinese aged 45 years and above were living with any DR, among whom the most were in South Central China and the least were in Northwest China. Collectively, these data suggest a considerable burden of DR in China.To the best of our knowledge, this systematic review and meta-analysis provides a comprehensive estimation of the prevalence, risk factors and burden of DR in China. Although this study is subsequent to the first synthesized analysis by Liu and colleagues, many new merits are highlighted . The priBefore interpreting the findings, potential limitations of this systematic review and meta-analysis should be carefully considered. First, the pooled prevalence of NPDR and PDR in general population might have been affected by publication bias. Generally, publication bias arises because statistically significant results are more likely to be published than non-significant results, combining these studies for analysis could, therefore, introduce bias ,46,47. UIn this study, significant heterogeneity was noted in pooling the prevalence rates of DR. The main sources of heterogeneity in the included studies pertained to the different characteristics of study population. After omitting each study at a time, the pooled prevalence of any DR was robust and consistent. The pooled prevalence of any DR in Chinese people with DM was lower in our study than that in the global DR study (18.45% vs 25.08%) . There aIn our analysis, the prevalence of any DR was found to peak between 60 and 69 years of age, which is in line with the age-specific prevalence estimates of DR among Americans ,49. In eGood glycemic control has long been recognized as one important factor for reducing vascular complications of DM, and it is also important in the prevention of DR ,58. In tThe increasing burden of DR might bring a higher pressure on available infrastructure and resources. Ideally, periodic eye examinations should be conducted by all patients with DM. Regular follow-up to detect significant retinopathy, together with prompt interventions when necessary, is believed to be the most effective method to reduce potential DR-related visual disabilities ,3,62. InWith new epidemiological investigations emerging, the results of this study should be updated in a timely and regular manner. In addition, there remains a genuine need for prompting international standardized DR classification systems in Chinese scientific society, to facilitate communication and comparison across the world.To conclude, this contemporary systematic review and meta-analysis estimated the prevalence, risk factors and burden of DR in China. The results from this study revealed a substantial burden of DR in China. Optimal screening of and interventions on DR should be implemented in the Chinese health system. Improved epidemiological studies on DR are still required to guide eye care programmes in China.


P = 0.01, I2 = 92.3%; AG vs. AA: OR = 1.34, 95% CI = 1.04-1.74, P = 0.03, I2 = 65.9%; AG + GG vs. AA: OR = 1.58, 95% CI = 1.11–2.25, P = 0.01, I2 = 84.4%), and the same results were obtained in the subgroup analysis. Moreover, the IL-10 -819 T > C polymorphism exhibited a significant, protective effect against cervical cancer. In summary, our meta-analysis suggests that IL-10 polymorphisms may play a variety of roles in regard to cervical cancer risk, especially in Asians.Previous studies have suggested that interleukin-10 (IL-10) polymorphisms may be associated with an increased risk of developing cervical cancer. However, the published results on this subject matter are controversial. The aim of this study was to conduct a meta-analysis of published reports to more precisely investigate the relationship between IL-10 polymorphisms and cervical cancer risk. Five online databases  were searched, and seventeen articles with sufficient quantitative information were included in our meta-analysis. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between IL-10 polymorphisms and cervical cancer risk. Publication bias, sensitivity and cumulative analyses were also performed to support our findings. Overall, there was a significant association between the IL-10 -1082A > G polymorphism and cervical cancer risk observed in the total population (G vs. A: OR = 1.60, 95% CI = 1.12–2.29,  Cervical cancer is the second most common form of cancer diagnosed in women and the third leading cause of death from cancer. This accounts for approximately 8% of total cancer cases and cancer deaths in women . In 2012In the last decade, numerous studies have suggested that certain cytokines may play critical roles in the processes of inflammatory cell infiltration and malignant cell transformation , 15. IntSingle nucleotide polymorphisms are one of the most common, heritable variations in the human genome, accounting for more than 90% of all variation . The IL-Therefore, we conducted the present meta-analysis to provide a more precise and comprehensive assessment of the relationship between IL-10 polymorphisms and cervical cancer susceptibility. This meta-analysis was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . No ethiInitially, 164 relevant articles were identified through our search strategy. The study selection procession is shown in Figure P = 0.01, I2 = 92.3%; AG vs. AA: OR = 1.34, 95%CI = 1.04–1.74, P = 0.03, I2 = 65.9%; AG+GG vs. AA: OR = 1.58, 95% CI = 1.11–2.25, P = 0.02, I2 = 84.4%) . Moreover, a significant risk of cervical cancer was also seen in all five genetic models for the HWE, the hospital control and the PCR genotyping groups .Publication bias was assessed with Funnel plots. Plot asymmetry was observed only in the AG+GG vs. AA model, which was redressed in the subgroup analysis by ethnicity   .P = 0.23; TC vs. TT: P = 0.06; CC vs. TT: P = 0.96; TC+CC vs. TT: P = 0.11; CC vs. TT+TC: P = 0.26)  revealed an increased risk for cervical cancer in the Caucasian population group. Additional subgroup analyses were conducted based on HWE status, the control design and the genotyping method, but no significant associations were observed. The pooled ORs did not exhibit any changes following sensitivity or cumulative analyses, and no publication bias was observed   . A similIn 2013, Ni et al. published the first meta-analysis examining the association between IL-10 gene polymorphisms and cervical cancer risk. Their meta-analysis included eight studies comprising 1,498 cases and 1,608 controls for the IL-10 -1082A > G polymorphism, as well as five studies involving 2,396 cases and 1,388 controls for the IL-10 -592C > A polymorphism . The resCompared with the previous meta-analyses, our meta-analysis relied on a more scientifically sound retrieval strategy and included more research studies  to accurately assess the associations between the IL-10 -1082A > G, -819T > C and -592C > A polymorphisms and cervical cancer risk. Our results suggest that the IL-10–1082A > G polymorphism may be associated with an increased risk of cervical cancer development. In contrast, the IL-10–819T > C polymorphism may have a protective effect against cervical cancer development, especially in Asian populations. In the stratified analysis, the heterogeneity between the included IL-10–1082A > G polymorphism studies was moderately, and successfully reduced by the subgroup analysis based on ethnicity. This suggests that ethnic diversity maybe a potential heterogeneity factor. Moreover, after conducting the sensitivity and publication bias analyses, no significant alterations or bias were observed for any of the three polymorphisms, presenting the stability of the results of our meta-analysis.To our knowledge, this is the first meta-analysis to examine the association between IL-10 polymorphisms and cervical cancer risk, including the three most common polymorphic loci . However, there are some limitations of this study that should be addressed. First, only seventeen publications were included in our meta-analysis. The limited number of studies and sample size for each polymorphic locus may reduce the reliability of the results and affect the assessment of associations between these IL-10 polymorphisms and cervical cancer susceptibility. Second, additional risk factors, such as smoking, drinking, and HPV infection, were not considered. The interactions between genetic and environmental factors and cancer development could not be evaluated in our analysis. Third, the association between the IL-10 -1082A > G, -819T > C and -592C > A polymorphisms and cervical cancer risk were analyzed separately, and the influence of the haplotype and gene-gene interactions was not analyzed due to an insufficient amount of data. Fourth, the heterogeneity that exists between the IL-10–1082A > G polymorphism studies could influence the current results and distort the conclusions. In this meta-regression analysis, we could not find the source of the heterogeneity, although it could be reduced in the subgroup analysis.In summary, our meta-analysis suggests that the IL-10–1082A > G and -819T > C polymorphisms are associated with cervical cancer susceptibility, but with contradictory effects. In contrast, no significant association was found between the IL-10–592C > A polymorphism and cervical cancer susceptibility.st, 2017) was independently performed by two of the authors, without restrictions on the geographic region or language of publications from the following online databases: PubMed, Embase, Science Citation Index (SCI), CNKI and Wanfang. References appearing in relevant reports and recent reviews were all screened to identify potential articles of interest. The search terms“Interleukin-10”, “polymorphism” AND “cervical cancer”, and the following search strategy were used : #1 Interleukin-10, #2 IL-10, #3 rs1800870, #4 rs1800871, #5 rs1800872, #6 #1 OR #2 OR #3 OR #4 OR #5, #7 polymorphism, #8 variant, #9 mutation, #10 #7 OR #8 OR #9, #11 cervical cancer, #12 cervical tumor, #13 cervical neoplasm, #14 #11 OR #12 OR #13, #15 #6 AND #10 AND #14.A comprehensive literature search  the study design had to be a case-control study (including retrospective or prospective studies); 2) the focus of the study had to be on IL-10 promoter polymorphisms ; 3) the case group had to include women with cervical cancer and the control group had to consist of women without cervical cancer; 4) the reports had to include sufficient information on the frequency distribution of different genotypes in order to calculate the odds ratios (ORs) and 95% confidence intervals (CIs); and 5) in the case that there were duplicate studies, we included the most recent or those with the largest samples sizes.Two investigators (Guo and Wen), independently extracted the following information from all of the included studies: first author, year of publication, study country or region where the study was performed, ethnicity , the source of the controls, the sample sizes of patients and controls, data on the frequency distribution of different genotypes, the Hardy-Weinberg equilibrium (HWE) for the controls, and the genotyping method. In addition, the modified Newcastle-Ottawa scale (NOS) was employed by the first two authors in order to evaluate the quality of the included studies . The scoQ test and the I2 statistic [P-value was more than 0.10 and the I2 was less than 40% [P value < 0.05 was considered significant.ORs with 95% CIs were calculated to assess the strength of the association between the IL-10 -1082A > G, -819T > C and -592C > A polymorphisms and cervical cancer susceptibility. For the IL-10 -1082A > G polymorphism, the five following genetic models were used: allele contrast model (G vs. A), co-dominant models (AG vs. AA and GG vs. AA), dominant model (AG+GG vs. AA), and recessive model (GG vs. AA+AG). The same genetic models were also used to assess the IL-10 -819T > C and -592C > A polymorphisms. Subgroup analyses were performed according to HWE status, ethnicity difference, control designs, and genotyping methods. Heterogeneity between studies was determined via a Cochran’s tatistic . A fixedthan 40% . Otherwithan 40% . Meta-rethan 40% , 58. All


CXCR4) synonymous polymorphism (rs2228014), and risk of cancer, but the results remained conflicting and controversial. Therefore, this study was devised to evaluate the genetic effects of the rs2228014 polymorphism on cancer risk in a large meta-analysis.Previous epidemiological studies have reported the relationship between CXC motif chemokine receptor 4  were searched for all relevant studies evaluating rs2228014 and susceptibility to cancer. In the analysis, pooled odds ratios (ORs) with its corresponding 95% confidence intervals (CIs) were calculated in 5 genetic models to assess the genetic risk. Egger regression and Begg funnel plots test were conducted to appraise the publication bias.Data on rs2228014 polymorphism and overall cancer risk were available for 3684 cancer patients and 5114 healthy controls participating in 11 studies. Overall, a significantly increased risk of cancer was associated with rs2228014 polymorphism in homozygote model  and in recessive model . When stratified by ethnicity, the results were positive only in Asian populations . Besides, in the subgroup analysis by source of control, the result was significant only in population-based control .CXCR4 gene is correlated with an increased risk of cancer, especially among Asian ethnicity. Large, well-designed epidemiological studies are required to verify the current findings.In general, our results first indicated that the rs2228014 polymorphism in  It has been suggested that CXCR4 plays an essential role in tumor progression including colorectal, breast, and oral squamous cell carcinoma, as all of them usually metastasize to CXCL12-expressing organs.–8 Data from in-vitro experiments as well as from murine in-vivo models, investigating the metastatic capability of CXCR4, underlined the vital role of CXCR4 for cancer cell malignancy, as activation of the 7-transmembrane G-coupled receptor CXCR4 by CXCL12 induced proliferation, invasion, migration, and angiogenesis of cancer cells.–12CXC motif chemokine receptor 4 , is found at codon 138.,14 Several molecular epidemiological studies showed that CXCR4 was highly mutated and had a pro-oncogenic role in cancers, including renal cell carcinoma, nonsmall cell lung cancer, oral cancer, hepatocellular carcinoma, acute myeloid leukemia, and breast cancer. However, other studies indicated that there was no significant association between rs2228014 polymorphism and cancer risk, such as endometrial carcinoma, bladder cancer, chronic lymphocytic leukemia, breast cancer, and prostate cancer. Because of relatively small sample sizes, these studies provided limited evidence and might have been underpowered to detect the overall effects. Therefore, we conducted this meta-analysis to obtain a more precise estimation from all eligible case–control studies.The human 22.1We systematically searched PubMed, EMBASE, and Web of Science comprehensively for all publications regarding the association between the rs2228014 polymorphism and cancer risk , by using the combinations of the following keywords: CXCR4, rs2228014, variants/polymorphism/polymorphisms/genotype/single nucleotide polymorphism (SNP), and cancer. Additional usable data were hand-searched from reference lists of original studies or review articles. Nevertheless, if several studies were performed on the same subjects, only the 1 with latest, and/or largest sample size would be involved. Ethical approval was not necessary, because this was a meta-analysis, including no direct handing of personal data or recruitment of subjects.2.2Studies involved had to satisfy the inclusion criteria: case–control design was utilized; the diagnosis of the patients with cancer should be pathologically confirmed and the controls were verified as free from any cancer; and sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI) was available. The major exclusion criteria were as follows: no obtainable genotype frequency data; duplicates of previous publication; and studies designed as a case–case or case-only study.2.3The identified studies were reviewed separately by 3 of the investigators  independently and carefully to determine whether an individual study was eligible for the analysis. These data were extracted from studies involved independently, and the disagreement was resolved by a discussion involving a senior investigator (KJ). All the following data were sought from each study and recorded in a standardized form: first author's name, year of publication, ethnicity of each study population, source of controls, sample size, genotyping method, number of cases, and controls, frequencies of rs2228014 in cases and controls, respectively, and results of the Hardy–Weinberg equilibrium (HWE) test.2.4 If existence of heterogeneity was detected, the random-effects model would be more appropriate.The pooled ORs with 95% CIs were applied to evaluate the strength of association between rs2228014C/T polymorphism and cancer susceptibility. The fixed-effects model (the Mantel–Haenszel method) and the random-effects model (the DerSimonian–Laird method) were separately employed to pool the data.P < 0.05 was set as the significance threshold. HWE was checked by the goodness-of-fit chi-square test, and a P < 0.05 was considered as a significantly selective bias.Sensitivity analysis was performed to assess the influence of individual studies on the pooled ORs, with the method of calculating the outcomes again by omitting 1 single study each time. After that, subgroup analyses according to ethnicity, source of controls, and sample size were further carried out to identify the potential association for each subgroup. If total quantity of case and control was larger than 700, the sample size would be regarded as large. The reverse was true for small sample size. Begg funnel plots and Egger linear regression method were taken to estimate the publication bias, and a P values were all 2-sided and regarded as statistically significant if less than 0.05.Stata software  was employed in the whole statistical analyses. 33.1–25 and the details of each study were recorded in Table  The sample size ranged between 2831 and 5967. Two genotyping methods were utilized in the studies, including TaqMan and polymerase chain reaction restriction fragment length polymorphism.The flowchart of study exclusion and inclusion with specific reasons is indicated in Fig. 3.2CXCR4 rs2228014 polymorphism association, the carriers of TT genotype held higher cancer risk than carriers of CT/CC genotype, especially in Asian ethnicity.The key outcomes of the meta-analysis of the association between rs2228014 polymorphism and cancer risk were listed in Table 3.3Heterogeneity between studies was observed in overall genetic models but decreased through subgroup analyses. The analysis of Galbraith manifested that between-study heterogeneity was not prominent.3.4 the corresponding pooled ORs were not qualitatively altered when it was omitted. The sensitivity analysis indicated that our results were reliable.We conducted sensitivity analyses by repeating the meta-analysis while sequentially omitting the studies included (1 omitted each time). The sensitivity analysis under homozygote model for rs2228014 polymorphism association in the overall population is shown in Fig. 3.5PBegg  =  0.161; PEgger  =  0.062; model: TT vs CC). The overall results revealed that our results were statistically reliable  have been identified that may influence cancer risk.,14 Although the hypothesis of the neutral theory of molecular evolution—that some categories of mutation, like synonymous mutations, have too small an effect on fitness to be affected by natural selection—seems intuitively reasonable, over the past few decades the theory has been not applicable. New evidence indicates that even some synonymous mutations are subject to constraint, often because they affect splicing and/or messenger RNA stability.As the exclusive receptor for CXCL12, CXCR4 has been verified to play an essential role in the progression and prognosis of tumor.CXCR4 rs2228014 polymorphism is associated with the risk of cancer have yielded conflicting results,–25 which might partially own to the relatively small sample size of individual study, the different distributions of patients or controls, different cancer types, and the various methodologies. Meta-analysis as a powerful tool can provide more reliable results than a single study especially in explaining controversial conclusions. To achieve a better understanding of the association between rs2228014 and cancer risk, we conducted this meta-analysis with larger sample size and subgroup analyses, which provided new evidence for the susceptibility and etiology of cancer. To the best of our knowledge, our meta-analysis, on the basis of 11 case–control studies , is the first, also the largest and most comprehensive assessment to investigate this association and the final results showed that rs2228014 polymorphism was associated with an increased cancer risk.To date, many case–control studies that have been carried out to investigate whether Interestingly, stratified analysis by ethnicity indicated that, among Asians, the rs2228014 polymorphism was significantly associated with increased cancer risk under all the 5 genetic models. The differences between Asians and other races may be partly due to the different genetic backgrounds and environments or lifestyles. In the subgroup analysis of different sources of controls, evidence of an association between the rs2228014 polymorphism and an increased cancer risk was found in the population-based studies, but not in the hospital-based studies (HB). In the stratified analysis of ethnicity, our results showed that the T allele of rs2228014 had a 2.01-fold risk of cancer in overall populations, a 2.43-fold risk (95% CI: 1.21–4.91) in Asian populations. Lack of association among HB subgroup was probably due to the fact that the controls recruited from hospital could not represent the general population well. In the future, well designed studies with large sample size might provide more precise results about such associations.CXCR4 gene and the increased susceptibility to human cancers, especially in Asian population. Second, the comprehensive inclusion criteria and articles on wide range of cancers enhanced the power and persuasion of our conclusion. Lastly, no publication bias was detected, indicating that the results might be unbiased.Some advantages could be emphasized in our meta-analysis. First, this research shed lights on the relationship of a synonymous polymorphism in Despite the overall sufficient and robust statistical evidence generated through this analysis, some limitations should be addressed. To begin with, in the stratified analyses, the sample size of some subgroups was relatively small, with limited statistical power to explore the real association. In addition, included studies are still so limited that we cannot perform subgroup analysis for different cancer types although it is well known that 1 SNP may act different roles in different kinds of cancer. What is more, the lack of original data in some valuable researches restricted us to continue investigating some potential interactions, such as age, sex, family history, environmental factors, and lifestyle. Accordingly, it is required that a more precise analysis could be performed if individual data were available.5CXCR4 gene rs2228014 polymorphism might be a potential detecting index for the risk of cancer in the future. In order to acquire a more integrate understanding of the correlation between rs2228014 polymorphism and cancer susceptibility, several recommendations have been suggested as follows: (first) though the sufficient evidence has been achieved in this meta-analysis, more studies by standardized unbiased methods are required, which can provide more detailed individual data of high quality. (second) Effects of different gene polymorphisms need to be combined, due to the intricate genetic background of cancer development, including single-candidate genes as well as complex epigenetic process. In consequence, a single gene polymorphism is difficult to be identified responsible for cancer. (third) More comprehensive and generalizable conclusions are expected to achieve among various ethnic groups.The outcomes of the present meta-analysis demonstrate that the The authors thank Dr Xiao Li of the Department of Urology, The First Affiliated Hospital of Nanjing Medical University, for his contributions and guidance.


The results of genome-wide association studies (GWAS) and case-control studies performed to investigate the associations between epidermal growth factor receptor (EGFR) gene polymorphisms and glioma risk are controversial. The aim of this systematic review and meta-analysis is to determine whether EGFR gene polymorphisms are associated with glioma risk by searching ‘PubMed’, ‘EMBASE’, ‘Web of Science’, ‘Cochrane Library’ and ‘China WeiPu Library’ to retrieve studies that investigated associations between EGFR gene polymorphisms and glioma risk. Four GWAS containing 35 studies and 7 case-control studies meeting the inclusion criteria were finally recruited, and 11 single-nucleotide polymorphisms (SNPs) were analyzed. The results showed a significant positive association between rs730437/rs845552 and glioma risk in Asians, and a significant negative association between them in Caucasians. In addition, rs11506105 was significantly associated with an increased risk of glioma in both Asians and Caucasians, and rs11979158 decreased the risk of glioma in Caucasians. However, no significant association was observed between rs12718945/rs17172432/rs4947492 and glioma risk in Asians, between rs2252586 and glioma risk in Caucasians, and between rs3752651 and glioma risk in either Asians or Caucasians. In conclusion, different SNPs in EGFR gene might have different impacts on the risk of glioma in various ethnicities, which offers new insights into the treatment with a target-oriented approach. Glioma is the most common primary brain tumor, with about 20000 new cases per year in the United States –3. It haIt is generally believed that glioma is very difficult to be cured because many currently available drugs that are effective against systemic cancers are unable to cross the blood-brain barrier . To prevIn recent years, more and more attentions have been paid to the roles of genetic factors (genes and gene polymorphisms) in the etiology, pathogenesis and complexity of glioma. Researchers attempt to explore new revolutionary therapeutic approaches based on these molecular genetics , 12. SevSingle-nucleotide polymorphisms (SNPs) in EGFR gene are getting increasingly recognition of importance in the etiology, development and progression of glioma, as it has been verified in many studies that EGFR gene plays a key role in human tumors by regulating cellular processes . Wang etA systematic online search was conducted to find out all the eligibile studies. Databases including ‘PubMed’, ‘EMBASE’, ‘Web of Science’, ‘Cochrane Library’ and ‘China WeiPu Library’ were searched. All the studies recruited in our meta-analysis should investigate associations between EGFR gene polymorphisms and glioma risk. We used the following search terms to identify all the relevant studies:  AND (‘glioma’) AND (‘SNP’ OR ‘polymorphism’ OR ‘single nucleotide polymorphism’ OR ‘variation’). There were no language restrictions in our searching procedure. The reference lists of the recruited studies, reviews or conference reports were also searched to find out other eligible studies that might be omitted in databases. Furthermore, we examined the reviews and comments to further search out eligible studies so that no possible studies would be missed.The inclusion criteria of were as follows: (1) case-control studies that explored the relationships between EGFR gene polymorphisms and glioma risk or GWAS; (2) cases: patients diagnosed as glioma; controls: cancer-free subjects ; (3) evaluation of glioma risk and at least one EGFR gene polymorphism was analyzed and reported; (4) reporting detailed numbers or frequencies of alleles or genotypes in at least one EGFR gene polymorphism in both cases and controls subjects. The exclusion criteria were as follows: (1) case reports or reviews; (2) no currently available or sufficient data; (3) duplicated studies.Two authors extracted the general information and data in each study. If there was any disagreement, a third author would extract them, which was solved by consensus. The following data were collected: authors, publication year, types of article, number of studies in eligibile references, population ethnicities, sample size, source of controls, Hardy-Weinberg equilibrium (HWE) and SNPs studied in articles. We would contact the corresponding authors if there were incomplete data in recruited studies. In addition, whether the genotype distributions followed the HWE in controls was also explored.2 metric value. If I2 value was > 50% or P < 0.10, OR was pooled by random effects models; otherwise, OR was pooled by the fixed effects model. We also assessed the HWE for the control group in each article; a P value > 0.05 suggested that the controls followed a HWE balance. Furthermore, we also performed a sensitivity analysis to detect whether each study has a great impact on pooled results. Besides, subgroup analysis was also performed according to the ethnicity. Stata 14.0 software was used to calculate the pooled results, and a P < 0.05 was considered as statistically significant.We calculated the odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations between EGFR gene polymorphisms and glioma risk. We used allele contrast model to assess the main results of the strength of associations between EGFR gene polymorphisms and glioma susceptibility. Other genetic models were also calculated to evaluate the relationships between EGFR gene polymorphisms and glioma risk. We examined the heterogeneity of included studies using Q statistical test and IA total of 11 studies –24 incluvs. CA/AA: OR = 1.38, 95% CI = 1.18–1.61, P < 0.001) in the overall populations, as shown in Table P < 0.001; CA vs. AA: OR = 1.36, 95% CI = 1.15-1.62, P < 0.001; CC vs. AA: OR = 1.82, 95% CI = 1.44-2.31, P < 0.001; CC/CA vs. AA: OR = 1.47, 95% CI = 1.25-1.72, P < 0.001; CC vs. CA/AA: OR = 1.52, 95% CI = 1.23-1.89, P < 0.001), while there was no significant association between EGFR rs730437 polymorphism and glioma risk in Caucasians , as indicated in Table rs730437 was significantly associated with the increased risk of glioma , and a protective contributor in Caucasians . However, there was no significant association between rs1468727 and glioma risk in the overall populations . All the data are shown in Table rs1468727 was a risk contributor to glioma susceptibility in Asians , rs9642393 might increase the risk of glioma in Asian populations , and decrease the risk of glioma in Caucasian populations .As shown in Table vs. AG/AA: OR = 1.35, 95% CI = 1.13-1.60, P = 0.001), Asian populations  or Caucasian populations .Our results also illustrated a significant association between rs11506105 and glioma risk in either overall populations ; while no significant association between rs845552 and glioma risk was observed in either Caucasian populations or overall populations , although no study was performed to detect the relationship between rs11979158 and glioma risk in Asian and overall populations , as shown in Table P > 0.05). All the data were shown in Table We failed to find any significant association between rs12718945, rs17172432 and rs4947492 and glioma risk in Asian populations, and between rs2252586 and glioma risk in Caucasians  and glioma risk in Asians. Therefore whether rs11979158 and rs2252586 may be contributors to glioma in Asians needs more investigations. Second, we did not explore the association between EGFR gene polymorphisms and different subtypes of glioma such as astrocytoma, oligoastrocytoma and GBM due to the insufficient original data. As the biological characteristics may vary in different subtypes, whether EGFR gene polymorphisms play different roles in different subtypes of gliomas needs further investigation. Third, some other EGFR gene polymorphisms such as rs7809394, rs10225877 and rs917881 were not analyzed in our study, because only one study reported the relationships between these polymorphisms and glioma risk. Therefore, more larger-scale studies with sufficient origional data should be further performed.Different SNPs in EGFR gene might have different impact on the risk of glioma in various ethnicities. These EGFR gene polymorphisms provide new insights in treating glioma.