Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. Autism spectrum disorders (ASDs) include autistic disorder (or classic autism), Asperger syndrome, pervasive developmental disorders-not otherwise specified (PDD-NOS), and childhood disintegrative disorder. As a childhood disease, autism is characterized by three core symptoms with impaired reciprocal social interaction and communication, a pattern of repetitive behavior and/or restricted interests –4. CliniDespite the lack of success in identifying the candidate genes which are responsible for the majority of ASD cases, epigenetic modifications of genes important for normal brain development and growth and cognitive function and behavior are involved in the etiology of ASDs. The term epigenetics means reversible heritable changes in gene expression regulation by modulating rather than by changes in the nucleotide sequence of a gene . AbnormaMTHFR) gene in folate metabolism may contribute to epigenetic mechanisms that modify complex gene expression, thus causing autism. MTHFR is one of the most important enzymes in the folate pathway. It converts 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate and regulates the intracellular flow of folate. C677T polymorphism in the MTHFR gene  is associated with a decrease in enzymatic activity to 35–70% in homozygotes [In recent years, some studies have revealed that polymorphisms of the genes are involved in the folate/homocysteine pathway as risk factors for autistic children –17. TherA222V, rs01133 is  MTHFR functional polymorphisms in autism and ASD [ MTHFR C677T polymorphism in a total of 98 autistic patients in Turkey.To date, there have been some case-control studies of and ASD , 15, 17.MTHFR is probably relevant in autism and we wanted to test our study group in Turkey. The study group was collected between May 2009 and May 2014. Patients were diagnosed by using the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV) and DSM-V [n = 98) comprised patients with autism and the control group (n = 70) comprised healthy children. There were 81 simplex families and 8 multiplex families in the case group. The control group was randomly selected and matched for age and sex for this study. In the study group, there were 71 males and 27 females. Information spanning a minimum of three generations of family history was obtained and simplex families did not reveal further cases of ASDs. All of the cases met the clinical criteria for autism found in the absence of a known etiology with detectable chromosomal defects using the standard karyotyping procedure and other genetic syndromes, that is, Fragile-X syndrome, Rett's syndrome, and Angelman syndrome. The control group consisted of 46 males and 24 females. This study was approved by ethical committee in Erciyes University and informed consent was obtained from all the participants.nd DSM-V , 20. Exc MTHFR C677T polymorphism (rs1801133) was examined by polymerase chain reaction- (PCR-)restriction fragment length polymorphism (RFLP). PCR fragments were amplified from 20 ng of each DNA sample in 50 μL PCR mix containing 0.5 U/mL Taq DNA polymerase, 1.5 mM MgCl2, 1X concentration of the buffer, 2.5 mM concentration of deoxynucleotide triphosphate (dNTP), and 10 pmol of each primer. Primer sequences are summarized in  Hinf I restriction enzyme and checked with 3% agarose gel electrophoresis [Two mL blood samples were obtained from patients with autism and from the control group. Genomic DNA was extracted according to the standard protocols of Roche .phoresis . Every Pq-q plots were examined; also Shapiro-Wilk's test was applied. To compare the differences between disease groups, Mann-Whitney U test was used for continuous variables. Pearson's chi-square analysis was used to determine the relationship between genes in ASD. Odds ratios with 95% confidence intervals were calculated for risk assessment. Analyses were conducted using R 3.1.0 (http://www.r-project.org/) software by considering a P value less than 0.05 statistically significant.To assess the data normality, histogram and P = 0.237). The heterozygote genotype was associated with 1.3-fold (95% CI: 0.70–2.41) risk for autism and this risk was not statistically significant ).In the study group, there were 71 males (72.4%) and 27 (27.6%) females. The mean age of cases was 6.0 (3.8–8.0). There were 46 (65.7%) male controls and 24 (34.3%) female controls. The mean age of controls was 5.0 (4.0–6.0). There was not any significant difference between the groups for this polymorphism  did not differ from that in the controls (43.2%). The allele and genotype frequencies of the polymorphism in multiplex families were very similar to those in the control group. Finally, they suggested that reduced MTHFR activity is a risk factor for autism only in simplex families [ MTHFR gene in three groups of children diagnosed with autism (n = 15), Asperger syndrome (n = 5), and PDD-NOS (n = 19) and their age- and sex-matched controls (n = 25). The results showed a normal distribution of the C677T polymorphism in children with ASDs, but the frequency of the T allele was slightly more prevalent in autistic patients. They, therefore, thought that a possible role for the alterations in one carbon metabolism existed in the pathophysiology of ASDs [Liu et al. selected two common polymorphisms (C677T and A1298C) to test simplex and multiplex ASD families because of the association of reduced MTHFR enzyme activity. The T allele was more prevalent in children with an ASD (42.9%) compared to controls (32.3%) and this finding differed significantly from those in the comparison group with a families . Paşca erols n = . The res MTHFR 677 was significantly higher in children with autism (16.1%) than in controls (8.6%). According to this finding, Guo et al. suggested that MTHFR C677T is a risk factor for autistic patients in their population [P = 0.77). The genotype distribution did not reveal significant differences between cases and controls (P = 0.72) [In a Chinese Han population, the frequency of the TT genotype ofpulation . One hunpulation . In anot = 0.72) . MTHFR 677TT would exhibit more behavioral problems and/or more severe problematic behaviors than homozygous wild-type (CC) individuals. Their results did not suggest such a relationship between genotypes for MTHFR 677CT and developmental regression. They also showed that four behaviors  were more common and problematic among those with a heterozygous state as compared to homozygous wild-type individuals [ MTHFR 677CT and 1298AC polymorphisms were tested in Korean population. 677CT/1298AC was significantly associated with 2.11-fold increased risk of ASD compared with the combination of 677CC/1298AA genotypes [ MTHFR polymorphisms (C677T and A1298C) and the risk of ASD. Eight case-control studies (1672 patients with ASD and 6760 controls) were included for this meta-analysis. Their results show an association of MTHFR C677T polymorphism with increased susceptibility to ASD [An interesting study was carried on about behavioral problems in children with autism. Goin-Kochel et al. hypothesized that autistic children who carry the homozygous genotype for theividuals . For Parenotypes . A meta- MTHFR 677CT revealed 44 (44.9%) children with the CC genotype, 51 (52%) children with the CT genotype, and 3 (3.1%) children with the TT genotype in cases. We did not detect any homozygous polymorphism in the control group and this result was not significantly different between the groups. T allele frequency was higher in the patients. Our results were in accordance with dos Santos et al.'s study. Thus, contrary to some studies we could not demonstrate an association between this polymorphism and autism. One limitation of this study is the small sample size of autism families. Differences due to the genetic heterogeneity of autism, ethnic variation, recruiting strategies, family types (simplex or multiplex), sample size, and/or other factors that we could account might give these results.In our study genotyping for MTHFR SNPs . We recommend investigating this risk in a larger sample size with the same diagnostic criteria, same ethnicity and paying great attention to gender distribution to get reliable results in ASD.We suggest replicating the study with larger well-characterized simplex families with nonautistic siblings, to determine the presence or absence of commonCOMT) pathways should be investigated in future studies.Other environmental risk factors should be considered; in particular, the methylation/transsulfation and/or catecholamine-O-methyltransferase (


In the dose–response analysis the summary relative risk was 1.11  per 10 cigarettes per day and although there was indication of nonlinearity there was a dose-dependent positive association with increasing number of cigarettes smoked per day. The current meta-analysis provides evidence of an increased risk of gallbladder disease associated with tobacco smoking.Tobacco smoking has been inconsistently associated with gallbladder disease risk.To clarify the association we conducted a systematic review and meta-analysis of cohort studies published on the subject. We searched the PubMed and Embase databases for studies of smoking and gallbladder disease up to January 9th 2015. Prospective studies were included if they reported relative risk estimates and 95 % confidence intervals of gallbladder disease associated with current, former or ever smoking and by number of cigarettes per day. Summary relative risks were estimated by use of a random effects model. We identified ten prospective studies including 59,530 gallbladder disease cases among 4,213,482 participants that could be included in the meta-analysis. The summary RR was 1.19  contains supplementary material, which is available to authorized users. Gallbladder disease is a major cause of morbidity in the US and in the Europe. The prevalence of asymptomatic gallbladder disease ranges between 10–30 % within these populations . Of digeTobacco smoking is believed to affect the hepatobiliary system and has been associated with increased risk of liver  and gallWe developed a systematic review protocol for the project. Pubmed and Embase databases were searched up to January 9th 2015 for eligible studies. As part of a larger project on risk factors for gallbladder disease we used wide search terms PubMed search:  AND . We followed standard criteria for conducting and reporting meta-analyses . In addiWe included published prospective studies that investigated the association between smoking and the risk of gallbladder disease, gallstones, or cholecystectomies. Adjusted estimates of the relative risk had to be available with the 95 % CIs in the publication. For the dose–response analysis a quantitative measure of the smoking level had to be provided. We identified ten relevant prospective studies that could be included in the analysis –24. A liThe following data were extracted from each study: The first author’s last name, publication year, country where the study was conducted, study period, sample size, sex, number of cases, smoking type, cigarettes per day, relative risks and 95 % confidence intervals for the highest versus the lowest level of smoking and variables adjusted for in the analysis. One reviewer extracted the data (DA) and they were checked for accuracy by a second reviewer (LJV). Any disagreements were resolved by discussion.We calculated summary relative risks for the highest versus the lowest level of smoking using the random-effects model by DerSimonian and Laird  which taTo investigate whether the number of cigarettes smoked per day was associated with gallbladder disease we used the method described by Greenland and Longnecker  to condu2 statistics [p < 0.05 considered statistically significant. I2-values of 25, 50 and 75 % indicates low, moderate and high heterogeneity, respectively [Heterogeneity between studies was evaluated using Q and Iatistics . All staectively . We condectively .p < 0.10 was considered to indicate possible publication bias as the tests have low power when the number of studies is low. The statistical analyses were conducted using the software package Stata, version 9.0 software .Publication bias was assessed using Egger’s test  and BeggOut of a total of 12,747 records identified by the searches, we identified 10 prospective studies –24 invol2 = 46.9 %, pheterogeneity = 0.09)    . There was no evidence of publication bias in the analysis of current smokers, p = 0.98 and p = 0.99 with Egger’s test and with Begg’s test respectively, former smokers, p = 0.46 and p = 0.71, or ever smokers, p = 0.58 and p = 0.37, respectively, although there was possibly slight asymmetry in the funnel plots . However, this was driven by one or two outlying studies which did not affect the overall summary estimates.Six cohort studies –21 were 2 = 33 %, pheterogeneity = 0.23) per 10 cigarettes per day Below is the link to the electronic supplementary material.


The effects of the microRNA (miRNA) processing genes Gemin3 and Gemin4 on cellular signaling pathways could have a major impact on the risk of cancer. Several studies concerning the association between the Gemin3 rs197412, Gemin4 rs7813 and Gemin4 rs2740348 polymorphisms with cancer susceptibility have been published. The present meta-analysis summarized this evidence and evaluated the precision of these relationships. Relevant studies  without language restriction were identified using the PubMed, Web of Science and China National Knowledge Infrastructure (CNKI) on-line databases. The data were extracted from the eligible studies and were processed using Stata 12.0 software. Seven studies  indicated that the rs7813 polymorphism was significantly associated with increased cancer risk . Six studies  indicated that rs2740348 was associated with an increased cancer risk . However the rs197412 polymorphism was not associated with an increased cancer risk (OR = 0.97 95% CI [0.80–1.19]). Our results suggest that the Gemin4 rs7813 T > C and rs2740348 G > C polymorphisms are associated with cancer susceptibility. Approximately 1,665,540 new cancer cases and 585,720 cancer deaths were projected to occur in the United States in 2014 . Cancer The incidence of cancer is a process that involves a variety of factors, and abnormal cell signal transduction pathway activity is considered to be one such essential factor. Identifying genetic markers of cancer susceptibility might help to reduce cancer mortality via early diagnosis and personalized therapy .MicroRNAs (miRNAs) are a group of small non-coding molecules that can affect the stability of mRNA to induce mRNA cleavage or translational repression . MiRNAs In the biogenesis of miRNAs, the Argonaute proteins (Ago1-4) along with Gemin3 and Gemin4 selectively bind to the guide strand to facilitate the formation of an miRNA-RNA-induced silencing complex (RISC) . Single Relevant works were identified using the Web of Science, PubMed and CNKI online databases . We used the following keyword search terms: “cancer or carcinoma,” “tumor or tumour”, “Gemin3, Gemin4, Ago1-4,” “rs197412, rs7813, rs2740348,” and “polymorphism or SNP.”The PRISMA guidelines were used as the main criteria in our study, which employed a 27-item checklist and a four-phase flow diagram . We usedThe selection detail of studies for our analysis based on the following criteria: (i) studies that assessed an association between the rs197412, rs7813 and rs2740348 polymorphisms and cancer risks; (ii) studies that contained related casecontrol studies; and (iii) studies that contained available and useful data on genotype frequency for estimating odds ratios (ORs) and 95% confidence intervals (95% CIs). The exclusion criteria included the following: (i) reviews, conference abstracts, or animal studies; (ii) studies lacking sufficient data for a meta-analysis; and (iii) studies reporting data that overlapped with already included studies. Study quality was assessed using the Newcastle-Ottawa Scale (NOS).The NOS scores ranged from 0 to 9, and an NOS score greater than or equal to 6 was considered to indicate a high-quality study.P-values and Z scores were the indices used to evaluate the low-frequency variants in meta-analysis  test for heterogeneity. Generally, if I2 >50%  at a significance level of As shown in the flow chart , 292, 28Z-score = 2.75, P-value = 0.006) . However, in the Caucasian subgroup, the pooled OR was positively associated with cancer risk . A fixed-effects model was used to evaluate both the Asian and Caucasian subgroups according to study heterogeneity (I2 < 50). The results of the meta-analysis of the Gemin4 rs2740348 SNP revealed increased cancer risk for GG relative to GC + CC   (The main characteristics and results of the eligible studies are summarized in = 0.006) . In a su= 0.044) . Due to = 0.799) .I2 = 18.5% and the P-value of a Q test for heterogeneity (Ph) = 0.289. Sensitivity analysis revealed that the pooled ORs were not changed by removing any single study  showed any evidence of publication bias. In the funnel plot analysis of rs2740348 (P = 0.612) showed any evidence of publication bias. In the funnel plot analysis of rs197412 (P = 0.920) showed any evidence of publication bias.In the funnel plot analysis of rs7813 , neithers2740348 , neitherrs197412 , neitherOur results suggest that the Gemin4 rs7813 T > C and rs2740348 G > C polymorphisms are associated with cancer susceptibility.As mentioned previously, miRNAs are emerging as critical regulators of gene expression, as they have been shown to modulate approximately 1/3 of the human genome . The relIn our meta-analyses, we found that the Gemin4 rs7813 and rs2740348 SNPs were significantly associated with the risk of cancer. P-values and Z-scores of meta-analyses are widely used to evaluate low-frequency and rare variants. In our study, the P-values for rs7813 (P = 0.006) (P = 0.007) and rs2740348 (P = 0.044) enhanced the reliability of our results. We did not show the results for HWE in To date, no meta analysis has evaluated the relationship between polymorphisms in Gemin3 or Gemin4 and cancer risk. Our study selected seven articles, with a pooled total of 2,588 cases and 2,549 controls, relevant to the relationship between the rs7813 SNP and cancer risk, and we found a significant increase in cancer risk for TT relative to TC + CC . The results regarding the Gemin4 rs2740348 SNP were controversial. For this analysis, 6 articles were included, and the pooled OR was a critical value . However, we did not conclude that this SNP may increase the incidence of cancer. Had we collected more related studies and a larger sample size, our data would have been more convincing. The Next, we investigated the Gemin3 rs197412 SNP, which is a key indicator of renal cell carcinoma. In this meta-analysis, however, rs197412 was not associated with increased cancer risk. In addition, we searched for articles related to the Gemin3 rs197414 and rs197338 SNPs, and the Gemin4 rs3744741 and rs4968104 SNPs. However, we identified fewer than five articles, which was insufficient for us to evaluate the precise relationship between these SNPs and cancer risk. However, we found several articles that reported an association between Gemin polymorphisms and several chronic diseases, such as hepatitis B . The relI2) test was used to evaluate study heterogeneity. In our study, the I2 values were small; thus, the effect of ethnicity was small. Additional subgroup analyses by ethnicity would supplement our results.The method of selection of a fixed-effects or random-effects model did not follow the gold standard. Generally, most recent studies have used one or a combination of the traditional fixed-effects or random-effects models. However, some drawbacks regarding combining meta-analysis results from multi-ethnic genome-wide association studies (GWASs) persist . These mWith respect to methodological quality, the greatest limitation of our study was the relatively small population size, which may lead to type II error. Each polymorphism can produce discrepant effects between different genetic backgrounds . AlternaIn conclusion, our meta-analyses provided statistical evidence that the Gemin4 rs7813 and rs2740348 SNPs can predict cancer prognosis. However, we need to perform further research on the association of the rs2740348 SNP with cancer risk to provide more powerful evidence of a true association. We hope that the results of our study will aid in identifying the roles of miRNAs in cancer prevention and control.10.7717/peerj.1724/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.1724/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.1724/supp-3Supplemental Information 3Click here for additional data file.


ERCC1 gene may alter DNA repair capacity and modulate cancer risk. The putative roles of ERCC1 gene polymorphisms in lung cancer susceptibility have been widely investigated. However, the results remain controversial.Excision repair cross-complimentary group 1 (ERCC1) is an essential component of the nucleotide excision repair system that is responsible for repairing damaged DNA. Functional genetic variations in the ERCC1 polymorphisms: rs11615 (T>C), rs3212986 (C>A), rs3212961 (A>C), rs3212948 (G>C), rs2298881 (C>A).An updated meta-analysis was conducted to explore whether lung cancer risk could be attributed to the following Several major databases  and the Chinese Biomedical database were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of associations.ERCC1 rs11615 with increased risk for lung cancer . However, such an association was disproportionately driven by a single study. Removal of that study led to null association. Moreover, initial analyses suggested that ERCC1 rs11615 exerts a more profound effect on the susceptibility of non-smokers to lung cancer than that of smokers. Moreover, no statistically significant association was found between remaining ERCC1 polymorphisms of interest and lung cancer risk, except for rs3212948 variation .Sixteen studies with 10,106 cases and 13,238 controls were included in this meta-analysis. Pooled ORs from 11 eligible studies  suggested a significant association of ERCC1 rs3212948 G>C, but not others, is a lung cancer risk-associated polymorphism. Carefully designed studies with large sample size involving different ethnicity, smoking status, and cancer types are needed to validate these findings.Overall, this meta-analysis suggests that  ERCC1 gene that compromise DNA repair capacity may be a potential risk factor for tobacco-induced cancers. Therefore, potential associations between ERCC1 gene polymorphisms and cancer risk have evoked great interest. Due to lack of non-synonymous single nucleotide polymorphism (SNP) in the coding region of the ERCC1 gene, most studies have focused on the rs3212986 (3′UTR C8092A) and synonymous rs11615 (exon 4 T19007C) polymorphisms, which are believed to influence transcript stability and mRNA levels ERCC1 variants, associations of three other ERCC1 polymorphisms (rs3212961 (17677A>C), rs3212948 G>C, and rs2298881 C>A) with lung cancer risk have also gained increasing attentions. Therefore, we conducted this updated meta-analysis to reassess the associations of the first two common polymorphisms in the ERCC1 gene and lung cancer risk, and explore the influence of the other three polymorphisms on predisposition to lung cancer.It has become clear that the susceptibility to disease varies from one individual to another. Some heritable characteristics that shape the effects of environmental exposure may contribute to the variable susceptibilities among people. Smoking highly increases risk of lung cancer by up to 20 folds since many carcinogens in cigarette smoke can be converted into reactive metabolites in human body. These reactive products  can potentially damage cellular DNA and cause the formation of DNA adducts via covalent binding or oxidation. The resulting adducts are carcinogenic and may block the transcription of critical genes or result in mutations at hot spots ERCC1 or excision repair cross-complimentary group 1”, “DNA repair”, “polymorphism or variant or variation” and “lung cancer or tumor or carcinoma or neoplasm”. Publications written in Chinese were also searched from the Chinese Biomedical (CBM) database (http://cbmwww.imicams.ae.cn/cbmbin) (1978–) to increase the coverage of our current study using the combination of terminologies: “ERCC1”, “polymorphism” and “lung cancer” in Chinese. In addition, references of the retrieved research or review articles on this topic were manually reviewed to identify extra eligible studies. Publication search was initiated on October 12, 2013, and last search was performed on November 15, 2013.A systematic literature search throughout the MEDLINE, EMBASE and Scopus databases was performed with the use of the following search terms: “ERCC1 polymorphisms.Selected studies must meet the following inclusion criteria: 1) studies investigating any type or mixed types of lung cancer : adenocarcinoma, squamous carcinoma, and large-cell carcinoma, etc.), regardless of smoking status; 2) original research studies written in English or Chinese, 3) case-control, nested case-control, or cohort study, and 4) adequate information to calculate odds ratio (OR) and 95% confidence interval (CI). Exclusion criteria were: 1) duplicate data, 2) abstract, case report, comment, review, and editorial, 3) lack of sufficient genotyping data, and 4) studies involving subjects with family history or cancer-prone disposition. In the case of studies with overlapping subjects, the latest and/or largest study was chosen. Studies in which the genotype frequencies of the control group departed from Hardy-Weinberg equilibrium (HWE) was excluded from the final analysis, unless there was further evidence validating HWE from another ERCC1 polymorphisms for cases and controls, and main findings. In the case that studies included subjects of different ethnic groups, data were obtained separately for each ethnic group and labeled as Caucasian or Asian.Information extraction was conducted individually by two investigators (Zhu JH and Hua RX) from each eligible study. The main information comprises first author, year of publication, country of origin, ethnicity, cancer type, source of controls , genotyping method, number of cases and controls, genotype counts of five ERCC1 polymorphism genotypes and corresponding ERCC1 mRNA expression levels in 270 lymphoblastoid cell lines. Genotype data of ERCC1 polymorphisms and ERCC1 mRNA expression information were retrieved from HapMap website (http://www.hapmap.org) and SNPexp online tool (http://app3.titan.uio.no/biotools/help.php?app=snpexp), respectively. These resources facilitate researchers to determine the correlation of HapMap genotypes in a genomic region of interest and gene expression levels http://www.sanger. ac.uk/resources/software/genevar/).The biological plausibility of our findings was investigated by correlating respective ERCC1 polymorphisms and lung cancer risk. Letters V and W represented variant and wild alleles of each polymorphism. Different genetic models were adopted during risk estimation: homozygous (VV vs. WW), heterozygous (WV vs. WW), recessive (VV vs. WV/WW), and dominant (VV/WV vs. WW) model. A chi-square-based Q-test was used to check heterogeneity assumption. A P-value of >0.10 for the Q test suggested the absence of heterogeneity across the studies, and then the fixed-effects model (the Mantel–Haenszel method) ERCC1 polymorphism was checked by the Pearson's goodness-of-fit chi-square test. Student's t test and analysis of variance test were used to evaluate the differences in the relative mRNA expression levels among different genotype groups. All analyses were performed by using STATA version 11.0  and SAS version 9.1 . All statistical analyses were two-sided, and P<0.05 was considered significant.Crude odds ratio (OR) with 95% confidence interval (CI) were used to access the association between each of the five ERCC1 rs11615 polymorphism et al.ERCC1 polymorphism of interest and lung cancer risk. Studies, inspecting the associations between multiple ERCC1 genetic variations and lung cancer risk were divided into several sub-studies, each of which encompassed the analysis of a single polymorphism. Genotyping in these 16 studies was performed via different methods, details of which were listed in et al. et al. Literature search initially produced 129 articles. After screening and reviewing articles for study eligibility, 113 articles were excluded due to review articles or non case-control studies, overlapped participants, failure to report genotype distribution data, and other reasons described previously ERCC1 rs11615 polymorphism and lung cancer risk was statistically significant  with moderate among-study heterogeneity  , and then significance of the association no longer existed  . Stratif existed . This stFurthermore, four of eleven publications including six studies  reported genotype distributions of rs11615 polymorphism for smokers and non-smokers. With these extra information based on smoking status, stratified analyses by smoking status showed that the association of the rs11615 polymorphism with lung cancer risk was stronger in non-smokers than in smokers : 2.39 (1.47–3.88)/2.16 (1.41–3.30); heterozygous, 2.39 (1.44–3.95)/1.77(1.21–2.60); dominant, 2.40 (1.49–3.85)/1.94 (1.36–2.79)) without substantial heterogeneity ,Table 2.ERCC1 rs3212986 polymorphism with risks for lung cancer, 6 eligible studies with 6,639 cases and 8,630 controls were pooled together for analysis et al. To investigate potential associations of ERCC1 rs3212961 in the lung cancer risk were available ERCC1 rs3212961 polymorphism with overall lung cancer risk  without substantial between-study heterogeneity without obvious heterogeneity , P = 0.41; recessive: OR = 1.10, 95% CI: 0.91–1.32, P = 0.322. Risk estimates suggested that ERCC1 rs2298881 is not a risk-associated polymorphism in lung cancer . The publication bias did not alter conclusion, because results in all comparison models unequivocally suggested that the pooled OR for the association was not statistically significant. Furthermore, no publication bias was detected for associations of rs3212986 polymorphism with lung cancer risk .Begg's funnel plot and Egger's test were conducted to detect the publication bias of the meta-analysis. The shapes of the funnel plot for the l models . Nonethecer risk , which wERCC1 rs3212986 and rs11615 may affect transcript stability and mRNA levels, respectively ERCC1 transcript correlate with genotypes of these two polymorphisms. Given subjects in our meta-analysis were from Chinese and Caucasian populations, we performed the correlation analyses for CHB (Chinese), CEU (Caucasian), and a combination of these two populations, respectively. Information on genotype of rs11615 polymorphism and corresponding ERCC1 mRNA expression was available for 32 CC (GG), 55 TC (AG), and 37 TT (AA) individuals. For ERCC1 rs3212986 polymorphism, there were 6 AA, 48 AC, and 70 CC carriers with expression data (ERCC1 transcript showed a trend of decreasing from wide type (TT) to the homozygous variant (CC) genotype of rs11615 polymorphism in CHB population, the difference did not reach statistical significance. Overall, there was no significant difference in ERCC1 transcript expression levels among different genotypes of rs11615 polymorphism in CHB, CEU, and combined populations under all the genetic models. Similarly, genotype of ERCC1 rs3212986 polymorphism did not appear to correlate with mRNA expression level of ERCC1 gene, either. The effect of ERCC1 rs3212948 polymorphism in ERCC1 gene expression was also explored since it was suggested to associate with decreased lung cancer risk. Results indicated that rs3212948 was related to decreased expression levels of the ERCC1 gene in CHB, but increased expression in CEU.  (It was thought that ion data . Althoug 0.0538) .ERCC1 polymorphisms and lung cancer risk have been conducted, but yielded conflicting results. The current meta-analysis examined whether five most commonly studied ERCC1 polymorphisms  were associated with lung cancer risk. Association between ERCC1 rs11615 or rs3212986 polymorphism and risk of lung cancer is seemingly biologically worthy of approval, since these two polymorphisms have been thought to alter transcript stability and mRNA levels ERCC1 rs11615 polymorphism with lung cancer under the homozygous model with moderate corresponding among-study heterogeneity . Nonetheless, influence analysis unveiled that the association mainly arose from one study by Zienolddiny and colleagues ERCC1 rs3212986 polymorphism and lung cancer risk.Accumulating studies of the associations between ERCC1 rs11615 polymorphism and lung cancer risk et al. analyzed total 7 studies et al. showed conflicting evidence, whose meta-analysis focusing on the contribution of ERCC1 polymorphisms on overall cancer risk. Stratified analysis with 9 studies ERCC1 rs11615, but not rs3212986 polymorphism significantly increased lung cancer risk.Recently, several meta-analyses have reported conflicting conclusion regarding to the association between the et al. et al. ERCC1 rs11615 and lung cancer risk might be stronger in non-smokers than in smokers, which may be in accordance with the concept of genetic susceptibility that indicate individuals with predisposition to cancer tend to develop cancer when suffering low-dose hazardous exposure . However, due to relatively small sample size and selection bias, this result should be interpreted with caution. Fifth, when compared to the latest meta-analysis concerning ERCC1 rs11615 polymorphism ERCC1 rs11615 or rs3212986 polymorphism with corresponding ERCC1 mRNA expression levels were negative. These results provide evidence supporting our findings that these two ERCC1 polymorphisms were not associated with lung cancer susceptibility.Compared to these previous meta-analyses, the current study has several unique features regarding rs11615 polymorphism. First, three new studies ERCC1 rs3212961 polymorphism has been also well characterized. With 4 studies , this meta-analysis demonstrated no association between this polymorphism and lung cancer risk. We also evaluated two additional ERCC1 tagging SNPs (rs3212948 and rs2298881). Risk estimates suggested that ERCC1 rs3212948 is a protection-associated genetic variation in lung cancer, whereas no association was found for rs2298881. To our knowledge, this is the first meta-analysis that estimated associations of ERCC1 rs3212961, rs3212948 and rs2298881 polymorphisms with lung cancer risk. Nevertheless, correlation analysis between genotypes of rs3212948 polymorphisms and mRNA expression did not agree with association study. Results for correlation suggested that rs3212948 might decrease expression levels of the ERCC1 gene in CHB, but increase the expression in CEU . Overall, no significant correlation was found in combined CHB and CEU population. Several reasons may help to explain the discrepancy: 1) the number of available studies for rs3212948 was very few, and meta-analyses with more studies are needed to validate our findings on association. 2) with only three studies, we were unable to perform efficient stratification analysis by ethnicity to investigate the association between rs3212948 and lung cancer risk in either Chinese or Caucasian group. However, the results convey some important information: 1) ERCC1 rs3212948 polymorphism may influence mRNA expression and 2) the effect on mRNA expression is ethnicity-dependent. These findings may promote researchers to investigate biological function of ERCC1 rs3212948 polymorphism.ERCC1 gene polymorphism may play roles to different extents in smoked-related and non-smoked-related lung cancer; however, very few of the studies in this meta-analysis separately reported SNP genotype counts for smokers and non-smokers. Future investigator should carefully list genotype counts for smokers and non-smokers to allow such stratified analyses to be done.There are some limitations in the current up-to-date meta-analyses. First, this meta-analysis may have been limited by the small number of eligible studies available. In particular, there were only four, three, and four publications available for rs3212961, rs3212948, rs2298882 polymorphisms, respectively, which may have attenuated the statistical power. Second, the missing data regarding cancer stage and insufficient histological details may also have impacts on the interpretation. Third, publication bias was detected by Egger's test, while analyzing the association between rs11615 polymorphism and lung cancer risk under the homozygous and dominant models. Forth, due to the deficiency of information on age, sex, ethnicity, and exposures , conclusions could only rely on unadjusted ORs, which might suffer confounding bias. Ideally, to perform a more precise analysis, crude ORs should be adjusted by potential confounders, such as age, sex, and other environmental factors after study results are pooled together. Unfortunately, in most cases, meta-analyses had to present only unadjusted ORs for the following reasons: 1) not all studies included in the meta-analysis provided adjusted ORs, 2) the ORs published in different studies were not adjusted by the same potential confounders, 3) usually only aggregate data  but not individual data are available in the reports. Given these deficits, we cannot eliminate the possibility that the significant associations observed in the current analysis might result from chance. Therefore, these results should be interpreted with caution. Further carefully designed studies with large sample sizes of different ethnic populations are warranted to validate our findings. Finally, this meta-analysis has been limited by the failure to acquire genotype data for some planned subgroup analyses. Particularly, ERCC1 rs11615 and rs3212986 polymorphisms. We found that there was null association between these two polymorphisms and lung cancer risk, and that ERCC1 rs11615 may play a more profound role in lung cancer risk of non-smokers than that of smokers. Among the rest of polymorphisms, only rs3212948 polymorphism seemed to correlate with lung cancer susceptibility and act as a protective factor. Carefully designed studies with large sample size involving different ethnicity, smoking status, and cancer types are warranted to validate these findings.Collectively, with more studies incorporated, we were able to conduct a more precise and robust evaluation for Figure S1ERCC1 mRNA expression by the genotypes of ERCC1 rs3212948 polymorphism.(TIF)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


FokI polymorphism have been studied in relation to tuberculosis (TB) in many populations and provided inconsistent results. In this study, we carried out a meta-analysis to derive a more reliable assessment on FokI polymorphism and the risk of HIV-negative TB.Vitamin D receptor (VDR) gene FOKI association studies aimed at the risk of TB up to June 30, 2015. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to measure the strength of the models.The Embase, PubMed, and Cochrane Library databases were used to undertake a comprehensive systematic literature review of all current published VDR gene P<0.001; I2 = 29.5%, and P = 0.141 for heterogeneity) in the best genetic model (recessive model: ff vs. fF+FF). In the subgroup analysis by ethnicities, a significantly increased risk was found in the Asian group  in the recessive model. Similarly, significant associations were also found in the polymerase chain reaction-restriction fragment length polymorphism group, high-quality studies, and the population based or hospital based groups. Moderate heterogeneity was found in this study.A total of 14 studies  were retrieved in the meta-analysis. The pooled OR was 1.60 (95% = 1.28–1.97, FokI polymorphism contributes to increasing the risk of TB in HIV-negative individuals, especially in the Asian region. Further studies on this topic in other races are expected to be conducted in future.Our results suggested that VDR  Tuberculosis (TB) is a global public health problem and remains a great burden throughout the world, although there has been an overall decline in TB incidence and mortality to this date. In 2013, an estimated 9 million people developed TB, and 1.5 million died from the disease, including 360,000 deaths in HIV-positive people. Many countries have high rates of TB and HIV co-infection [Mycobacterium tuberculosis [FokI, BsmI, ApaI, TaqI). The polymorphisms of FokI of the VDR gene, which transition C to T  at the first of the two potential translation initiation sites in exon 2, is related to plasma vitamin D levels in TB patients [FokI have been studied in relation to TB in many populations [In recent years, there has been a significant improvement in our understanding that vitamin D can influence the pathophysiology and possible prevention of human disease. Vitamin D is now considered to be a key factor of the body’s defence against TB through its action of enhancing macrophage-mediated eradication of rculosis . It has rculosis . The vitulations –19.FokI polymorphism and the risk of TB has provided inconsistent results [FokI polymorphism was associated with TB risk with significant heterogeneity [FokI polymorphism and TB. Therefore, a meta-analysis was carried out to derive a more reliable assessment on VDR FokI polymorphism and the risk of HIV-negative TB.However, previous literature about the associations between  results –19. A progeneity , 21. Howogeneity . We hypoThis meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, includiFOKI association studies aimed at the risk of TB up to June 30, 2015. The search terms were used as follows: vitamin D receptor or VDR in combination with polymorphism, polymorphisms, and mutation or variant in combination with tuberculosis or TB or phthisic or phthisis. Two investigators (CX and PT) conducted an extensive literature search independently for all publications. Articles in reference lists were also hand-searched. Only English articles and human studies were searched.We used the Embase, PubMed, and Cochrane Library databases to undertake a comprehensive systematic literature review of all current published VDR gene FOKI polymorphism and the susceptibility to HIV negative-TB were selected. The inclusion criteria were as follows:Studies aiming to evaluate the association between VDR gene Case-control or cohort design studies had to include data regarding the baseline characteristics of the patients . In addition, the inclusion and exclusion criteria for recruiting TB patients had to be clearly indicated.All the patients in studies had to be HIV-negative.Studies had to offer the ability to extract data for calculating the odds ratio (OR), 95% confidence intervals (CIs), and Hardy-Weinberg equilibrium (HWE).DNA genotyping methods and the sources of cases and controls were stated in studies.Review articles, case reports, editorials, conference abstracts, letters and family-based studies were excluded.Two reviewers (CX and PT) independently assessed publications for inclusion in the review. Data extracted from eligible studies included the baseline characteristics, such as the first author’s name, publication year, country, ethnicity, total sample size, genotyping method, and source of control group. Details of TB types and genotype frequencies of cases and controls were obtained. HWE was calculated from genotype frequencies of controls. Investigators would try to contact the author to get the original data if the literature could not provide sufficient data. To determine the accuracy of the extracted information by the two investigators, they checked their data if there was a dispute at first. If the two investigators could not reach an agreement, discrepancies were then resolved through discussion by the review team.To assess the validity of each study, we applied the criteria predefined by Thakkinstian et al. , with soFOKI polymorphism and the susceptibility to HIV-negative TB including an allelic model (f vs. F), co-dominant model , a dominant model (ff+fF vs. FF), and a recessive model (ff vs. fF+FF). Unadjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to measure the strength of the models because it is difficult to get the all original data from authors.According to a previous meta-analysis , f is th1, OR2, and OR3 were calculated for the genotypes ff vs. FF (OR1), fF vs. FF (OR2), and ff vs. fF (OR3). These pairwise differences can be used to indicate the best genetic model, as outlined below:To dictate the best genetic model and avoid the problem of multiple comparisons, we applied the method for meta-analysis of molecular association studies . OR1, OR1 = OR3≠1 and OR2 = 1, then a recessive model is suggested.If OR1 = OR2≠1 and OR3 = 1, then a dominant model is suggested.If OR2 = 1/OR3≠1 and OR1 = 1, then a complete overdominant model is suggested.If OR1 >OR2>1 and OR1 >OR3>1 (or OR1<OR2<1 and OR1 <OR3<1), then a dominant model is suggested.If ORI2) statistics and classified as low (I2<25%), moderate (I2 = 25–50%), and high (I2>50%), with a cut-off P-value of 0.10. A random-effects model was conducted using the DerSimonian and Laird method to calculate the summary OR and the corresponding 95% CI; otherwise, a fixed-effects model (the Mantel—Haenszel method) was used [P-value <0.05 was considered out of HWE. We also carried out a subgroup analysis by ethnicity, genotyping method, source of controls, TB type, HWE, and score by quality assessment, respectively.Heterogeneity was assessed by a chi-squared Q test and I-squared  and RevMan 5.3 (Cochrane Collaboration). A P-value <0.05 was considered statistically significant.The search strategy identified 165 citations. Thirty-nine articles that were thought to be potentially eligible for inclusion were retrieved and evaluated after the titles and abstracts were reviewed, and 25 articles were excluded after full texts were reviewed according to the inclusion and exclusion criteria . Finally1 = OR3≠1 and OR2 = 1, and suggested the genetic model was most likely to be recessive. Therefore, the FF and fF genotypes were combined and compared with ff (ff vs. FF+fF). The pooled OR was 1.60 . Summary results of comparisons are listed in The estimated OR1, OR2, and OR3 were 1.69 (95% CI = 1.19–2.41), 1.06 (95% CI = 0.83–1.35), and 1.48 (95% CI = 1.13–1.95), respectively . These iI2 = 31.0%, and P = 0.150 for heterogeneity) in the recessive model. However, no significant associations were found in the African group . Because only one study was conducted in the South American population, the heterogeneity and pooled ORs could not be calculated. Significant associations were also found in the polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) group, high-quality studies, and the population based (PB) and hospital based (HB) groups  groups .FokI polymorphism and HIV-negative TB risk in recessive model. We first excluded the study of Selvaraj et al. [j et al. , which wPEgger’s test = 0.682, 95% CI = –2.078–1.406).FokI polymorphism and the risk of HIV-negative TB. Our results suggests that individuals with an ff genotype increased about 1.60-fold risk of TB compared with F carries (FF or fF genotype) in the HIV-negative population, and 1.82-fold in the Asian group. Moderate heterogeneity was found in this study.The identification of host genetic factors, such as human leucocyte antigens (HLA), cytokines, and receptors, have been studied extensively to determine susceptibility to TB , 31, 32.FokI polymorphism increasing the risk of TB is biologically plausible. Vitamin D is an important immunoregulatory hormone; 1,25(OH)2D3, the active form of vitamin D, modulates the production of monocytes, lymphocytes, and several interleukins and other cytokines, as well as various oncogenes and transcription factors via VDR. Upon binding to 1,25(OH)2D3, the VDR complex moves into the nucleus, where it regulates the expression of genes [VDR of genes . The actof genes . A signiof genes . The sigof genes . These sFokI polymorphism and the risk of HIV-negative TB. As a result, a significant association was found in the Asian group when the ff genotype was compared with the FF and fF genotypes , but not in the African and South American groups. However, there were only two studies focusing on African populations and one focusing on the South American population. In addition, we noticed that most of these studies from Asia were performed on Indian and Chinese populations. Considering that genetic background may be distinct among different populations, further studies on this topic in different ethnicities are expected to be conducted to strengthen our results.As we know, gene polymorphisms are complicated and fluctuating, mainly due to various races and regions. Moreover, the burden of TB is highest in Asia and Africa geographically . TherefoHeterogeneity is the most common problem when explaining the results of a meta-analysis. Moderate heterogeneity was found in this study. However, heterogeneity was significantly reduced compared with previous meta-analyses , 21. TheFokI polymorphism and TB. The main limitation of this study is that a more precise analysis could not be conducted of individual information, including other covariates such as age and sex, due to a lack in the original data of the reviewed studies. In addition, most of the case—control studies were conducted in Asians; thus, our results may be applicable only to this ethnic group. Finally, this study could not address gene—gene and gene—environment interactions.The strengths of this study include focusing on HIV-negative TB patients to avoid selection bias, and the heterogeneity was significantly reduced compared with previous meta-analyses. We also used the best genetic model to avoid the problem of multiple comparisons. Therefore, although our results were similar to those of previous meta-analyses , 42, we FokI polymorphism contributes to increasing the risk of TB in HIV-negative individuals, especially in the Asian region. Further studies on this topic in other races are expected to be conducted in future.In summary, our meta-analysis suggested that VDR S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


MDM43’-untranslated (3’-UTR) region creates a miR-191-5p or miR-887-3p targeting sites. This change results in decreased expression of oncogene MDM4. Therefore, we examined the association between this SNP and small cell lung cancer (SCLC) risk as well as its regulatory function in SCLC cells. Genotypes were determined in two independent case-control sets consisted of 520SCLC cases and 1040 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The impact of the rs4245739 SNP on miR-191-5p/miR-887-3p mediated MDM4 expression regulation was investigated using luciferase reporter gene assays. We found that the MDM4 rs4245739AC and CC genotypes were significantly associated with decreased SCLC susceptibility compared with the AA genotype in both case-control sets . Stratified analyses indicated that there was a significantly multiplicative interaction between rs4245739 and smoking (Pinteractioin = 0.048). After co-tranfection of miRNAs and different allelic-MDM4 reporter constructs into SCLC cells, we found that the both miR-191-5p and miR-887-3p can lead to significantly decreased MDM4 expression activities in the construct with C-allelic 3’-UTR but not A-allelic 3’-UTR, suggesting a consistent genotype-phenotype correlation. Our data illuminate that the MDM4rs4245739SNP contributes to SCLC risk and support the notion that gene 3’-UTR genetic variants, impacting miRNA-binding, might modify SCLC susceptibility.A functional rs4245739 A>C single nucleotide polymorphism (SNP) locating in the  Lung cancer is the leading causes of cancer death in the world, with more than1,000,000 deaths per year ,3. As a 2-terminal P53-binding domain with MDM2 and can inhibit activities of P53 in various malignancies [MDM4, also known as MDMX or HDMX, is a structurally homologous protein of MDM2. MDM4 shares an NHgnancies –17. As tgnancies .MDM43’-untranslatedregion (3’-UTR) rs4245739A>C SNP locating in the target binding site for two miRNAs (miR-191-5p and miR-887-3p) [MDM43’-UTR with the rs4245739C allele but not 3’-UTR with the A allele. This allelic miRNAs’ binding leads to elevated expression levels of MDM4 mRNA and/or protein among rs4245739A allele carriers with cancers [MDM4 rs4245739 A-allele is significantly associated with increased risk of both prostate cancer and breast cancer [MDM4rs4245739 SNP may contribute to SCLC susceptibility via allelic regulation ofmiR-191-5p and/or miR-887-3p binding affinity and, thus, MDM4 expression. In the current study, we conducted a two-stage case-control study of SCLC recruited from Jinan city  and Huaian city . Furthermore, to validate the biological function of this polymorphism, we investigated the allelic regulation of miR-191-5p and miR-887-3p on MDM4 in SCLC cells.There is an -887-3p) . miR-191 cancers . Two GWAt cancer ,24. Sevet cancer ,22,25,26This study consisted of two case-control sets: (i) Shandong case-control set: 320 SCLC patients from Shandong Cancer Hospital, Shandong Academy of Medical Sciences  and sex- and age-matched (±5 years) 640 controls. Patients were recruited between June 2009 and November 2014 at Shandong Cancer Hospital. Control subjects were randomly selected from a pool of 4500 individuals from a community cancer-screening program for early detection of cancer conducted in Jinan city as described in detail previously . (ii) JiMDM4 rs4245739A>C genotypes as described in detail previously [5′-AAGACTAAAGAAGGCTGGGG-3′ and 5′-TTCAAATAATGTGGTAAGTGACC-3′. Restriction enzyme MspI (New England Biolabs) was used to digest the PCR products and distinguish the rs4245739 genotypes. A 10% random sample was reciprocally examined by different person, and the reproducibility was 98.7%. Additionally, a 5% random samples were also tested via Sanger sequencing, and the reproducibility was 100%.PCR-based restriction fragment length polymorphism (RFLP) was utilized to determine eviously ,25,26. IMDM4 rs4245739A and rs4245739C allelic reporter constructs were prepared by amplifying part of the MDM43’-UTR region from subjects homozygous for the rs4245739AA or rs4245739CC genotype. The PCR primers used were as follows: 5′-AACTCTAGAGGTAGTACGAACATAAAAATGC-3′ and 5′-AACTCTAGACTGCATAAAGTAATCCATGG-3′, which includes the Xba I restriction site (underlined sequences). The PCR products were digested with Xba I (New England Biolabs) and ligated, respectively, into an appropriately digested pGL3-control vector (Promega). The constructs were designated aspGL3-rs4245739A and pGL3b-rs4245739C, respectively. The inserts were confirmed by DNA sequencing.The A firefly luciferase reporter plasmid , a renilla luciferase vector  plus 30 nMsmall RNAs   were co-transfected into SCLCH446 cells with Lipofectamine 2000 . Luciferase activity was determined at 48h after transfection using a luciferase assay system (Promega) as previously described –29. ThreMDM4 rs4245739 SNP between SCLC cases and controls were calculated using Pearson’s χ2 test. Associations between MDM4 rs4245739 genotypes and SCLC risk were estimated by odds ratio (OR) and their 95% confidence intervals (CIs) computed using unconditional logistic regression model. All ORs were adjusted for age, sex and smoking status, where it was appropriate. We tested the null hypotheses of multiplicative gene-covariate interaction and evaluated departures from multiplicative interaction models by including main effect variables and their product terms in the logistic regression model [P value of less than 0.05 was used as the criterion of statistical significance, and all statistical tests were two-sided. All analyses were performed with SPSS software package .As described in detail previously , 30–32, P = 0.615; Jiangsu set: P = 1.000). There was no significant difference between cases and controls in sex distribution . This indicates that the frequency matching was adequate (P<0.001). Similarly, there are more SCLC patients who smoking than controls in Jiangsu set . Additionally, more patients with limited disease were observed than among ones with extensive disease in two sets .The median age was 57 years  for the patients and 57 years  for the controls  (As shown in  df = 2) . Similar df = 2) .MDM4 rs4245739 A>C polymorphism and SCLC risk were calculated using unconditional logistic regression analyses  for developing SCLC, compared with subjects with the AA genotype. Significantly decreased SCLC risk was also observed among rs4245739 AC or CC carriers compared to the AA carriers . The associations of SCLC risk with the MDM4 rs4245739SNP were further validated in an independent Jiangsu case-control set. A significantly decreased SCLC risk was also associated with rs4245739 . In the pooled analyses, we found that the rs4245739 AC genotype had a 0.49-folddecreased risk for SCLC compared with the AA genotype , and the rs4245739 AC or CC genotype had a 0.50-folddecreased risk compared with the AA genotype   . All ORsMDM4rs4245739genotypes by stratifying for age, sex, smoking status and disease stage using the pooled data of two Chinese case-control sets (P = 0.003), but not in subjects aged older than 57 years . There was no significant gene-age interaction (Pinteraction = 0.274). A significantly decreased risk of SCLC was associated with AC and CC genotypes only among females , but not among males , compared with the MDM4rs4245739 AA genotype. No significant gene-sex interaction was observed (Pinteraction = 0.135). We did not find significantly decreased risk  for the carriers with AC and CC genotypes compared with individuals with the AA genotype in smokers. However, thers4245739AC and CC genotypes did show a 0.30-fold decreased risk to develop SCLC  compared with the AA genotype in nonsmokers. A multiplicative gene—smoking interaction existed (Pinteractioin = 0.048). Associations between rs4245739 AC and CC genotypes and SCLC risk were observed in both patients with the limited stage disease  or the extensive stage disease  (We further examined the SCLC risk associated with the rol sets . In stra= 0.040) .MDM4mRNA and decreased MDM4expression in multiple malignancies [MDM4 regulation in SCLC are still unclear. As a result, we examined whether there is an allele-specific effect of rs4245739polymorphismon MDM4 expression in SCLC cells by miR-191-5p and miR-887-3p. Relative luciferase expression assays indicated that miR-191-5p can significant lower luciferase activities in SCLC H446 cells transfected with rs4245739C allelic reporter constructs compared to negative control RNAs(P = 0.003)  (SNPrs4245739A>C could lead to higher affinity between miR-191-5p/miR-887-3p and gnancies . However= 0.003) . Similar= 0.014) . However= 0.014) .MDM4 rs4245739 functional SNP and SCLC risk via a case-control approach. We observed that individuals with MDM4 rs4245739 AC or CC genotypes show significantly decreased SCLC risk compared with the AA genotype carriers. To reveal miR-191-5p/miR-887-3p mediated allelic-regulation by this SNP, we examined luciferase activities in SCLC cells transfected with different allelic reporter constructs. The genotype-phenotype correlation analyses indicated that both miRNAs could inhibit MDM4 expression only in SCLC cells with C-allele constructs expression but not A-allele constructs. These results highlight the involvement of functional genetic variants in miRNA-binding sites in SCLC etiology.In the current study, we investigated the association between the MYCL1 3’-UTR, resulting in higher constitutive expression of MYCL1 [MDM43’-UTR SNP targeted by miRNAs is associated with SCLC susceptibility.Accumulated evidences demonstrated that genetic makeup might have direct contribution of to SCLC risk –35. InteMDM4rs4245739 polymorphism showed a consistent association with SCLC risk intwo independent case-control sets, which are unlikely to be attributable to unknown confounding factors due to having significantly increased odd ratios with small P values. In addition, the genotype-phenotype relationship between the rs4245739 polymorphism and reporter gene expression supports our conclusion. Moreover, the MDM4rs4245739 SNP might be a common genetic risk component for different cancers, which has been proved by our group and others via either candidate gene approach or GWAS [The  or GWAS –26. For  or GWAS , a maligMDM4 rs4245739 SNP was associated with a significantly decreased SCLC risk in Chinese Han populations. The associations between SNPs and SCLC risk are remarkable in nonsmokers. Given this fact, further efforts are needed to examine whether MDM4 rs4245739 genetic polymorphism can be used as a potential diagnostic marker of SCLC.In summary, our results suggested that functional


Ischemic stroke (IS) is responsible for a high death rate and for adult disability worldwide. MiR-146a (rs2910164), miR-149 (rs2292832), miR-196a2 (rs11614913) and miR-499 (rs3746444) are found to be associated with ischemic stroke. However, the results were inconsistent and inconclusive. The present study performed a meta-analysis to get a more precise and comprehensive estimation of the association between the four polymorphisms and IS risk. The databases Pubmed, Embase, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, and Chinese Biomedical Literature Database were searched for related studies. A total of five studies including 2230 cases and 2229 controls were identified for the meta-analysis. The results indicate that TT genotype and T allele of miR-149 (rs2292832) are associated with significantly lower risks of IS in a homozygous model (OR = 0.70) and an allelic model (OR = 0.86). No significant associations were found between miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) and IS susceptibility in any of the studies. However, subgroup analysis by sample size indicates a significant decrease in risks of IS for CC genotype and C allele of miR-146a (rs2910164) in the large sample size group. Therefore, miR-149 (rs2292832) might be recommended as a predictor for IS risk, while miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) are not. Being the most common kind of stroke, ischemic stroke (IS) is responsible for a high death rate and adult disability worldwide. The mortality rate was reported to be about 120–180 per 100,000 in China, and it has become the third leading cause of death in the USA, exceeding the death rate of heart diseases ,4.etc. Thus, in the present study, we included a total of 5 studies, which have 2230 cases and 2229 controls, to get a more precise and comprehensive estimation of the association between the four polymorphisms and IS.MicroRNAs are non-coding, small RNAs with lengths of about 22 nt, which regulate the expression of many genes at a post-transcriptional level by binding to the 3′-UTR of target genes ,6. A sliWe systematically searched the published studies in the electronic databases of Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Literature Database (CBM). The searched terms are as follows: (“Ischemic stroke”) and (“microRNA”) and (“polymorphism” or “mutation” or “variant” or “SNP” or “single nucleotide polymorphism”). There were no restrictions on language. The deadline for publication was 24 August 2015. All the results from the databases were screened. First, we screened the titles. If a title fulfilled our criteria, we then screened the abstract. We retrieved the full text if the abstract was in accordance with our interest. All eligible studies were retrieved manually for other potentially relevant studies from their references. We would have contacted the authors for related data if they were unavailable in the original publications.Inclusion Criteria: (1) a case-control design; (2) that the association between microRNA polymorphisms and IS risks has been evaluated; (3) that the genotype in the control group is in agreement with the Hardy-Weinberg equilibrium (HWE) ; and (4)Information was extracted from each eligible publication manually by two investigators independently (Y. Xiao and J. M. Li). For each study, the extracted information included first authors’ name, published year, country, ethnicity, genotype method, the source of control, sex and age match, and the genotype numbers of cases and controls. If there were discrepancies during data extraction, it would be resolved by a consensus achieved by a third author (M. H. Bao).et al. [The quality of included studies was evaluated according to the predefined scale for quality assessment provided by Jiang et al. . The sco2-test was used to evaluate the HWE of the control group polymorphism. If p < 0.05, it is considered to be deviated from HWE. To evaluate the association between microRNA polymorphisms and IS risk, the crude odds ratio (OR) with 95% confidence interval (CI) was used. The summary effect estimate OR was calculated using genetic models of homozygous, heterozygous, dominant and allelic model. The statistical significance was determined by the Z-test, and p < 0.05 was considered to be statistically significant. Subgroup analysis by sample size was conducted. Groups with total samples less than 1000 was treated as small or as large.The χI2 and 95% I2 was used to assess the degree of heterogeneity [I2 > 50%) or a moderate heterogeneity (I2 25%–50%) among the studies, the random-effects model (the DerSimonian and Laird method) was used for the meta-analysis [p < 0.05 was considered to be statistically significant [The Q-statistic was used to test for homogeneity, and the ogeneity . If theranalysis . Otherwianalysis . Sensitinificant . All staA total of 48 studies were obtained from the literature search after duplicates removed. Among them, 27 studies were excluded for irrelevance, 11 for being reviews, 5 for predicting other polymorphisms and IS. At last, five studies were evaluated as meeting the criteria, which included 2230 cases and 2229 controls. Among these studies, four are on the association between miR-146a rs2910164 and IS, two on the association between miR-149 rs2292832 and IS, four on the association between miR-196a2 rs11614913 and IS, and three on the association between miR-499 rs3746444 and IS. The PRISMA flow chart is shown in The results of meta-analysis for the association between miR-146a (rs2910164), miR-149 (rs2292832), miR-196a2 (rs11614913), miR-499 (rs3746444) and ischemic stroke risks are shown in vs. GG, OR = 0.61, 95% CI = 0.47–0.79, p = 0.0002), the dominant model  and the allelic model .Four studies with 1873 cases and 1856 controls were included in this analysis. No significant associations were found between rs2910164 and IS susceptibility in the overall analysis for all genetic models. However, subgroup analysis by sample size showed a significant decrease in risks of IS in large sample size groups in the homozygous model  and the allelic model . The same relation was found in the small sample size group.Two studies with 1035 cases and 926 controls were included in this analysis. A significant decrease in ischemic stroke risks was found in the homozygous model (TT vs. CC) and allelic models (T vs. C), we also conducted a meta-analysis using the fixed effects model. No significant difference between these two models were found .Four studies with 1873 cases and 1856 controls were included in this analysis. No significant associations were found in the overall analysis or subgroup analysis in any of the models, be they homozygous, heterozygous, dominant or allelic. Since a moderate heterogeneity was found in the large group of homozygous models  and miR-499 (rs3746444), we performed a subgroup analysis by sample size to explore the source of this heterogeneity. The results indicate that the sample size is the source of heterogeneity for miR-146 (rs2910164) and miR-499 (rs3746444) in every genetic model.The influence of each study on the summary effect estimate ORs and 95% CIs were evaluated by excluding one single study at a time using STATA 12.0 software. No significant altered summary effect estimate ORs were found in any of the genetic models for miR-146a (rs2910164), miR-149 (rs2292832), miR-196a2 (rs11614913) and miR-499 (rs3746444).p values for Egger’s linear regression tests are shown in We performed the Begg’s funnel plot and Egger’s test to evaluate the publication bias. The The main findings of the present meta-analysis are that the TT genotype and the T allele of miR-149 (rs2292832) are associated with significantly lower risks of IS in the homozygous model (OR = 0.70) and the allelic model (OR = 0.86). There were no significant associations found between miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) and IS susceptibility in any of the studies. However, subgroup analysis by sample size indicates a significant decrease in risks of IS for the CC genotype and the C allele of miR-146a (rs2910164) in the large sample size group.Significant heterogeneity was found in the meta-analysis for miR-146a (rs2910164) and miR-499 (rs3746444). Thus, we conducted a subgroup analysis by sample size and observed that sample size was the source of the heterogeneity. However, only one study was included in the small sample size subgroup of miR-499, and two studies were included in the large sample size group of miR-499. For miR-146a, there were only two studies in either of the small and large sample size groups. Thus, further studies are needed to confirm these results. In the sensitivity analysis, no significant changes were found after omitting one study at a time, indicating the relative stability and credibility of the results of our meta-analysis.Previous studies have demonstrated that the mutation in pre-miRNA of miR-146a, miR-149, miR-196a2 and miR-499 decrease the mature miRNA levels ,19,20. TOur meta-analysis did not find significant associations between miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (rs3746444) and IS susceptibility in any of the studies. However, in the subgroup analysis, the CC genotype or C allele of miR-146a (rs2910164) were related to, and decrease the risk of, IS in the large sample size group as we previously reported . MiR-146Our meta-analysis did not find associations between miR-196a2 rs11614913), miR-499 (rs3746444) and IS. However, these two SNPs have been demonstrated to be related to other human diseases, including congenital heart disease , coronar913, miR-The results of the present meta-analysis should be interpreted carefully because of the following limitations. Firstly, the number of patients was relatively small, which may influence the outcomes. After a very comprehensive literature search from several different databases, only a total of five studies were included in the present meta-analysis. Among the studies, four are on the associations between miR-146a rs2910164 and IS (1873 cases and 1856 controls), two on the association between miR-149 rs2292832 and IS (1035 cases and 926 controls), four on the association between miR-196a2 rs11614913 and IS (1035 cases and 926 controls), and three on the association between miR-499 rs3746444 and IS (1505 cases and 1476 controls).The second limitation is that the clinicpathological characteristics or disease subtypes are limited in most of these studies. Thirdly, ischemic stroke is a multi-factorial disease influenced by both genetic and environmental factors. The gene-gene and gene-environment interactions may play important roles in the functions of these four polymorphisms, but most studies lack the information about environmental exposure and multiple SNPs in miRNA-encoding genes. The fourth limitation lies in the ethnicity of the subjects. All the patients in the present study were Asians, and this limited the general application of the results to other populations.In conclusion, the current meta-analysis suggests a decreased risk of IS for the TT and T allele of miR-149 (rs2292832), while miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) are not associated with the risk of IS. Thus, miR-149 (rs2292832) might be recommended as a predictor for susceptibility of IS. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity among study designs. Further studies are needed to evaluate the associations between rs2910164 and these two diseases, especially in a large sample size, in Caucasians, and with clinic-pathological characteristics.


N-nitrosodimethylamine (NDMA)—were included. The summary relative risk of stomach cancer for the highest categories, compared with the lowest, was 0.80 , 0.69–0.93) for dietary nitrates intake, 1.31  for nitrites, and 1.34  for NDMA . The study type was found as the main source of heterogeneity for nitrates and nitrites. The heterogeneity for NDMA could not be eliminated completely through stratified analysis. Although significant associations were all observed in case-control studies, the cohort studies still showed a slight trend. The dose-response analysis indicated similar results as well. High nitrates intake was associated with a weak but statistically significant reduced risk of gastric cancer. Whereas increased consumption of nitrites and NDMA seemed to be risk factors for cancer. Due to the lack of uniformity for exposure assessment across studies, further prospective researches are warranted to verify these findings.The potential associations between dietary consumption of nitrates, nitrites, and nitrosamines and gastric cancer risk have been investigated by several studies, but yielded inconclusive results. We conducted a meta-analysis to provide a quantitative assessment of their relationships. Relevant articles were identified by a systematic literature searching of PubMed and Embase databases prior to August 2015. Random-effects models were employed to pool the relative risks. A total of 22 articles consisting of 49 studies—19 studies for nitrates, 19 studies for nitrites, and 11 studies for  Over recent decades, the incidence and mortality rate of gastric cancer showed a modest decline globally. In 2012, an estimated almost one million new stomach cancer cases and 700,000 deaths occurred, making it the fifth most common malignancy and the third leading cause of cancer related deaths worldwide . TherefoN-nitrosodimethylamine (NDMA) is one of the most frequently occurring nitrosamines in our dietary foods [The typical diet in most countries contains nitrates, nitrites, and nitrosamines. Nitrates and nitrites occur naturally in fruit and vegetables, which are regarded as an important part of a healthy diet due to the powerful evidence of beneficial health effects against cancer ,5. In thry foods ,8. NDMA ry foods ,10.So far, numerous epidemiologic studies have been published which attempted to assess the potential risk of gastric cancer about the dietary nitrates, nitrites, and nitrosamines intake, but yielded discrepant findings. It would be of interest to evaluate, on the basis of current epidemiologic data, whether consumption of nitrates, nitrites, and NDMA had an effect on gastric carcinogenesis. To clarify their relations, we systematically reviewed all the available evidence and conducted a meta-analysis.N-nitrosodimethylamine OR NDMA) AND (gastric cancer OR stomach cancer). The manual search was supplemented by scrutinizing the reference lists from those retrieved articles to identify any relevant studies.We searched PubMed and Embase databases through August 2015 using the following search terms: (1) nitrate AND (gastric cancer OR stomach cancer); (2) nitrite AND (gastric cancer OR stomach cancer); and (3)  cohort or case-control design; (2) exposure of interest was dietary nitrates, nitrites, and NDMA intake; (3) the endpoint of interest was gastric cancer; (4) risk estimates with corresponding 95% confidence intervals (95% CIs) were provided; (5) published in English. When study populations were overlapped or duplicated in some studies, we chose the most complete and suitable research. Three authors evaluated the retrieved literature and any discrepancy was resolved through discussion.Two investigators using a standardized form to extract the following characteristics independently: first author’s name, publication year, population information, study location and period, sample size, follow-up years, nitrates and nitrites and NDMA intake assessment, and relative risk (RR)/hazard ratio (HR)/odds ratio (OR) with 95% CI from the most fully adjusted model for each category.Quality of the included studies was assessed using Newcastle-Ottawa Scale (NOS) with a score ranging from 0 to 9 . Each st2-based Q and I2 index. If three or more studies were available for the same characteristic, subgroup analyses were conducted.RR was used to measure the association between the dietary nitrates, nitrites, and NDMA intake and the risk of stomach cancer. Because the absolute risk of gastric cancer was low, OR and HR approximated the RR . Consideet al. to calculate the risk trend [For the dose-response analysis, we used the method proposed by Orsini sk trend . This mep < 0.05 was considered statistically significant.Meta-regression was employed to explore the possible heterogeneity, and study design, geographic area, and publication year were examined in the model. We also undertook sensitivity analysis to evaluate whether a single study could affect the overall outcome. Publication bias was assessed by funnel plot, with Egger’s regression asymmetry test and Begg’s adjusted rank correlation test, and the Duval and Tweedie “trim and fill” method was performed if bias was detected . All anaAs indicated above, the scope of this meta-analysis was the association between dietary nitrates/nitrites/NDMA intake and stomach cancer. The cases should be confirmed with reliable medical records such as surgical, pathology reports or linkage of authoritative tumor registries. The methods of exposure ascertainment will be extracted, which could vary considerably by the following factors: estimates from various food items and based on different food composition databases.Based on the search strategy, a total of 22 articles consisting of 49 studies were included in our meta-analysis . Of the versus the lowest categories, the summary RR was 0.80 . To explore the heterogeneity, we conducted subgroup analysis according to some key characteristics. In stratified analysis by study design, significant inverse association was observed in population-based case-control studies  with acceptable heterogeneity . Stratifying by geographic area, the RR was 0.79  in Europe. Besides, the associations between nitrates intake and risk of stomach cancer were similar in these subgroups , with obvious evidence of heterogeneity . Four papers (seven studies) were included in the dose-response analysis for NDMA [pnon-linearity < 0.001), following an increase in the risk of NDMA intake up to 0.12 μg/day (Four articles (7 studies) were eligible for the dose-response analysis of dietary nitrates intake and gastric cancer risk ,20,25,32for NDMA ,20,27,282 μg/day C.2). When all the variables  in the meta-regression model, the τ2 was reduced from 0.041 to 0.009 for nitrites, and from 0.139 to 0.026 for NDMA. Moreover, we found that study type was the main source of heterogeneity for nitrites, which interpreted 89.1% (0.041/0.046) of the τ2. Although geographic area could explain 92.1% (0.128/0.139) of the τ2 for NDMA, the subgroups stratifying by this variable still had non-negligible heterogeneity.As shown in et al. seemed to cause the heterogeneity [I2 = 8.8%, p = 0.349), and the summary RRs were 0.82  in the overall study and 0.79  in the case-control study. et al. influenced the overall pooled estimates for the association between NDMA intake and gastric cancer [I2 = 46.7%, p = 0.050).We confirmed the associations between dietary nitrates, nitrites, and NDMA intake and gastric cancer risk were relatively stable using sensitivity analysis. After removing one study at a time, the ranges of pooled RRs were 0.67–0.97, 1.10–1.57, and 0.97–1.89 for nitrates, nitrites, and NDMA, respectively . As showogeneity . This phc cancer . After tp = 0.047; Begg, p = 0.327), nitrites , and NDMA . Adjusting the possible publication bias for nitrates using “trim and fill” method did not influence the conclusion  and a number of oxygen atoms (O); and the chemical symbols are NOosamines . In our osamines . Besidesnclusion . Whereasnclusion ,19,20,40I2 = 0.0%, p = 0.849) [In the present study, high nitrates consumption demonstrated a protective effect for gastric cancer, in line with some previous studies ,29,34. B= 0.849) ,19,20,33Helicobacter pylori infection is a well-known risk factor for the development of distal gastric cancer. In this meta-analysis, only three case-control studies concerned this problem [Strengths of our meta-analysis included the large number of total subjects , dose-response relationship, reliable sources of heterogeneity, and the stable results in the sensitivity analysis. Here, some limitations were pointed out as follows. First, food frequency questionnaires were used to record the usual dietary consumption and classify them to estimate daily nitrates, nitrites, and NDMA intake. As a result, measurement error in different studies was inevitable, which might contribute to attenuation of the true relationship . Second, problem ,32,34. LAs diet is a very complex exposure variable, knowledge of beneficial factors and risk factors provide us an opportunity to improve heath and even prevent cancer. According to the report from WCRF/AICR , non-staIn summary, this meta-analysis suggested that dietary nitrates intake was associated with a reduced risk of gastric cancer, and high consumption of nitrites and NDMA could increase the risk. Considering the limitations and confounding factors, we could not absolutely confirm the reliability of these findings. More well-designed large prospective studies are needed to help us understand these substances in the etiology of gastric cancer.


A meta-analysis was performed to assess the association between healing rate, avascular necrosis (AVN) of femoral head and two reductions-open reduction internal fixation (ORIF) and closed reduction internal fixation (CRIF) for femoral neck fracture.2-based Q statistic. Egger’s regression analysis was used to evaluate publication bias. Statistical analysis was performed by Stata 10.0 software.A literature-based search was conducted to identify all relevant studies published before September 10, 2013. The odd ratio (OR) and 95% confidence interval (CI) were used for estimating the effects of the two reduction methods. Data were independently extracted by two investigators who reached a consensus on all of the items. The heterogeneity between studies was examined by χWe examined 14 publications. The results of the present meta-analysis showed that AVN of femoral head were significant associated with the two reductions , while the healing rate were not .The present meta-analysis indicated the risk of AVN of femoral head was significant higher after CRIF fixation compared with ORIF, but no association between the healing rate and the two reductions for femoral neck fracture. Femoral neck fracture, known as hip fracture, occurs in the proximal end of the femur near the hip, and is often due to osteoporosis. The incEmergency internal fixation is one of the main options for the treatment of displaced femoral neck fractures. It conthttp://www.cqvip.com/) and Wanfang database (http://www.wanfangdata.com.cn/) on line were searched using “open reduction”, “closed reduction” and “femoral neck fracture” as key words. There was no language restriction. The search was completed on September 10, 2013.PubMed, MEDLINE, PMC, Embase, Vipbrowser database  and 95% confidence intervals (CIs) were computed by the fixed-effects method of Mantel-Haenszel (Peto method) under no heterogeneity between studies. If significant heterogeneity existed between studies, then a random effects model of DerSimonian-Laird (D-L method) was applied for data synthesis. Egger's regression analysis was used to evaluate the publication bias. A p value less than 0.05 was considered statistically significant. Statistical analysis was performed by Stata 10.0 software.The heterogeneity between studies was examined by χtatistic and I2 tThe data selection process was displayed in Figure A total of nine studies-19 met tA total of eleven studies-18,20-24Femoral neck plays an important in weight bearing and movement. ORIF and CRIF are the two common techniques to cure femoral neck fracture. The results of the present meta-analysis showed that there was significant difference of AVN between ORIF and CRIF, while the healing rate was not.AVN of femoral head remains a major complication of femoral neck fractures. It is oNonunion is caused by a combination of unfavorable biomechanical and vascular conditions, ignoring general contraindications, and inadequate internal fixation. It alsoThe early treatment of femoral neck fracture is critical. CRIF is prior for patients with good blood perfusion of the femoral head while the ORIF should be se1ected for those with poor blood perfusion. It was There were several limitations in the present meta-analysis that should be noted. First, publication bias, an inherent limitation of all meta-analyses, may still exist because researchers are less likely to publish negative findings, although Egger’s regression analysis did not suggest publication bias in this study. Second, the confounding variables  were not adjusted because most of studies didn’t provide respective OR value or sufficient data for calculating OR. Besides, different types of reduction devices may affect the results. Third, we did not perform subgroup analysis for different type of femoral neck fracture because the classifications varied from different studies including Garden, PauwelsIn conclusion, our meta-analysis suggested that the risk of AVN of femoral head was significant higher after CRIF compared with ORIF, while there was no significant difference of the healing rate between the two reductions. ORIF offers advantage over CRIF in terms of AVN for treatment of the femoral neck fractures.Written informed consent was obtained from the patient for the publication of this report and any accompanying images.We certify that regarding this paper, no actual or potential conflicts of interests exist; the work is original, has not been accepted for publication nor is concurrently under consideration elsewhere, and will not be published elsewhere without the permission of the Editor and that all the authors have contributed directly to the planning, execution or analysis of the work reported or to the writing of the paper.WW and JW participated in the design of this study, and they both performed the statistical analysis. ZX and YZ carried out the study, together with WZ, collected important background information, and drafted the manuscript. HR, XC, and PW conceived of this study, and participated in the design and helped to draft the manuscript. All authors read and approved the final manuscript.Weiguo Wang and Junjie Wei: The first two authors should be regarded as joint First Authors.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/15/167/prepub