Although the relationship between a history of kidney stones and chronic kidney disease (CKD) has been explored in many studies, it is still far from being well understood. Thus, we conducted a meta-analysis of studies comparing rates of CKD in patients with a history of kidney stones.PubMed, EMBASE, and the reference lists of relevant articles were searched to identify observational studies related to the topic. A random-effects model was used to combine the study-specific risk estimates. We explored the potential heterogeneity by subgroup analyses and meta-regression analyses.I2 = 93.6%, P < 0.001). The observed positive association was observed in most of the subgroup analyses, whereas the association was not significant among studies from Asian countries, the mean age ≥50 years and male patients.Seven studies were included in this meta-analysis. Pooled results suggested that a history of kidney stones was associated with an increased adjusted risk estimate for CKD )], with significant heterogeneity among these studies (A history of kidney stones is associated with increased risk of CKD. Future investigations are encouraged to reveal the underlying mechanisms in the connection between kidney stones and CKD, which may point the way to more effective preventive and therapeutic measures. Kidney stones, solid concretions or crystal aggregations formed in the kidneys from dietary minerals in the urine, are common and responsible for significant morbidity. Racial differences are seen in kidney stone disease, primarily occurring in whites, followed by Hispanics, blacks, and Asians . Kidney This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement checklist  Stroup .PubMed and EMBASE were searched for observational studies to November 4, 2015, using the terms “renal stones” or “renal stone” or  “kidney stones” or “kidney stone” or “nephrolithiasis” and “chronic kidney disease” or “kidney failure” or “renal disease” or “kidney disease” or “renal insufficiency” or “renal failure” or “kidney failure” and “risk” or “incidence” or “epidemiology.” With these parameters, two investigators (WS and LL) independently filtered out all the eligible articles and hand-searched references of retrieved papers for additional available studies. Conflicting results achieved consensus by discussion.The inclusion criteria were: (1) case-control or cohort studies involving participants 18 years or older; (2) provided the multivariate-adjusted odds ratio (OR), risk ratio (RR), hazard ratio (HR), or standardized incidence ratio (SIR) with 95% confidence interval (CI), or sufficient information to calculate these; and (3) a comparison group made up of participants without kidney stones history was used.The exclusion criteria were: non-human studies, reviews, comments, editorials, case reports, and cross-sectional studies. If a cohort study was reported in more than one publication, we chose the latest article.The following data were extracted from the included studies: first author’s name, year of publication, study design, country, sample size, mean age, mean follow-up period, method of kidney stones and CKD diagnosis, participants with baseline CKD excluded (yes or no), and adjustment factors. When needed, we contacted the original author for clarification. The quality of each study was independently evaluated by two investigators (WS and YR) using the Newcastle-Ottawa Scale (NOS) . Article0) + (P0 × OR)] (where P0 is the incidence of the outcome of interest of the nonexposed group) (P < 0.10) and quantified using I2 index . The HR in each primary study was directly considered as RR . The OR d group) . The comI2 index , where 2I2 index . All anaAs shown in I2 = 93.6%, P < 0.001).As shown in I2 = 0%). In addition, when meta-regression performed, none of these variables had a significant interaction with the risk estimate   in individuals with kidney stones compared with cohort studies . Stratification based on sample size resulted in a pooled RR of 1.46 (95% CI [1.12–1.91]) in small sample studies and 1.49 (95% CI [1.10–2.03]) in large sample studies. Stratification based on region resulted in a pooled RR of 1.52 (95% CI [0.90–2.57]) in Asian populations and 1.44 (95% CI [1.20–1.73]) in Western populations. The observed positive association was also similar among studies with a mean age <50 years  and those with a mean age ≥ 50 years , although the latter did not reach statistical significance. Stratification based on follow-up time resulted in a pooled RR of 1.21 (95% CI [1.10–1.32]) for studies with a follow-up time <7.5 years and a pooled RR of 1.46 (95% CI [1.17–1.83]) for studies with a follow-up time ≥ 7.5 years. Stratification based on gender indicated that the pooled risks for CKD remained significant in female patients with kidney stones . However, the risk was slightly lower and did not remain significant in male patients with kidney stones . High heterogeneitywas present in subgroup analyses with the exception of case-control studies and mean follow-up time <7.5 years ( > 0.05) .Sensitivity analysis indicated that the estimate remained significant despite omission of any of the studies [RR varied between 1.38 (95% CI [1.16–1.65]) and 1.54 (95% CI [1.29–1.85])] . We did This study is the first meta-analysis to present the risk of CKD in patients with kidney stone history. We confirmed kidney stones were associated with an increased risk of CKD with a RR of 1.47 (95% CI [1.23–1.76]).As with other published meta-analyses of this type , our stuSimilarly, our study indicated that female patients with kidney stones showed a slightly higher risk for CKD than male patients. The increased risk was not significant in male patients with kidney stones. It is unclear if this represents a difference in underlying pathophysiology. Differences by sex are not infrequent. In Note that the CKD risk in patients with kidney stones becomes more substantial when we restrict analyses to cohort studies and studies with follow-up time ≥7.5 years. The risk of CKD was lower in cohort studies versus case-control studies (RR 1.35 vs 1.98), which is important as well-conducted cohort studies provide a higher level of evidence than case-control studies. It may be that the risk of CKD associated with kidney stones is not as high as our primary analysis would suggest. Regarding follow-up time, although not a significant difference, the risk was higher in studies with ≥7.5 years follow up versus those with <7.5 years, which may reflect the slowly progressive natural history of CKD.The pathophysiologic relation between kidney stones and new-onset CKD is rather unclear, but several potential reasons may explain the observed associations. First, for sterile stones, repeated episodes of obstruction associated with kidney stones may cause a sequence of tubular cell events followed by macrophage interstitial infiltration including an inflammatory cascade and interstitial fibroblast production, which can lead to glomerulosclerosis, reduced glomerular filtration rate, and renal insufficiency . Second,2 vs eGFR <60 mL/min/1.73 m2 differ substantially in terms of both prevalence and associated morbidity. Third, we did not have information on stone composition for most of participants with kidney stone history, and thus cannot evaluate the specific risk associated with different stone types. Similar limitations were seen on stone burden, medications, lithotripsy, other surgeries and genetic risk factors. Finally, although all the included studies controlled for several known risk factors for CKD, residual confounders may be present due to the observational nature of our study.Several limitations of this meta-analysis should be addressed. First, significant heterogeneity existed across the studies, thus, we conducted a subgroup analysis and meta-regression analysis. Unfortunately, we could not thoroughly explain the source of heterogeneity, suggesting other unknown confounding variables may be the source of heterogeneity. Second, the meta-analysis included studies with different study designs, follow-up time, diagnostic criteria, and adjusted confounders, which could introduce inherent limitations. For example, the cut-off points used to define CKD such as eGFR <45 mL/min/1.73 mIn conclusion, our study suggests a history of kidney stones is significantly associated with increased risk of CKD. Further efforts should be made to explore the potential biological mechanism to confirm these findings and they will stimulate the development of more effective preventive and therapeutic measures.10.7717/peerj.2907/supp-1Data S1Click here for additional data file.10.7717/peerj.2907/supp-2Supplemental Information 1Click here for additional data file.10.7717/peerj.2907/supp-3Supplemental Information 2Click here for additional data file.


ERCC5 rs1047768 and rs17655 polymorphisms influence the response to platinum-based chemotherapy. This meta-analysis was performed to summarize the scattered evidence regarding the association between these two polymorphisms and sensitivity to platinum-based treatment. Thirteen studies were included after a comprehensive literature search. The pooled odds ratios and 95% confidence intervals suggested that the C allele of the ERCC5 rs1047768 polymorphism is associated with elevated sensitivity to platinating agents, especially for Chinese patients. However, no difference among rs17655 genotypes could be detected.It is suspected that  Platinum-based chemotherapies are regarded as the most efficacious cancer treatment option. However, individual responses to these therapies greatly differ among patients due to multifactorial (intrinsic and acquired) resistance caused by genetic and epigenetic differences in sensitivity . PlatinuERCC5 rs1047768  polymorphism could yield differing survival outcomes, despite being a coding-synonymous polymorphism [ERCC5 rs17655  polymorphism was associated with an impaired prognosis [ERCC5 polymorphisms on the efficacy of platinum-based chemotherapy should be quantitatively evaluated.Excision Repair Cross-Complementation Group 5 gene ERCC5, 13q33.1) encodes a critical DNA repair enzyme involved in nucleotide excision repair (NER) function. Scattered evidences indicate the variants of the morphism . The corrognosis . The rs1q33.1 encrognosis . The effERCC5 polymorphisms and the sensitivity of platinum-based therapy [ERCC5 rs1047768 and rs17655 polymorphisms on the sensitivity to platinum-based chemotherapy in cancers.Many studies have tried to assess the association between the two  therapy , 15–26. ERCC5 rs1047768 polymorphism. For the rs17655 polymorphism, six studies with 973 samples met our predefined eligibility criteria. The selection process for eligible studies can be seen in Figure Our comprehensive literature search captured eligible 13 manuscripts , 15–26. When integrating all eligible studies, 622 good responders and 884 poor responders to platinum-based chemotherapy were pooled into the meta-analysis of the rs1047768 polymorphism. The pooled odds ratio (OR) and 95% confidence interval (CI) revealed the C allele carriers could be more sensitive to platinum-based chemotherapy treatment , country (China or others), and chemotherapy response evaluation criteria  or others) were the factors considered. ORs and 95% CIs were recalculated for every individual subgroup.An association between the rs1047768 polymorphism and sensitivity to platinum-based chemotherapy could be detected in both the NSCLC and non-NSCLC subgroups. There was an association in the Chinese population, but not in the subgroup for other nations. When stratifying according to chemotherapy response evaluation criteria, there was an association to only the recessive model in the RECIST subgroup. However, as for the non-RECIST subgroup, all four comparing models showed significant associations. No subgroup correlations were found for the rs17655 polymorphism.ERCC5 rs1047768 polymorphism. When stratified according to cancer type, heterogeneity was significantly relieved in both subgroups. However, neither country nor chemotherapy response evaluation criteria was identified as the contributing factor for between-study heterogeneity.Heterogeneity was only identified in the recessive model of the Our funnel plot analysis indicated a very small likelihood of publication bias in this study Figure . Our leaERCC5 rs1047768 polymorphism indicated that the C allele may promote sensitivity to platinum-based chemotherapy. However, the rs17655 polymorphism showed no difference among different genotypes.A predictive biomarker for sensitivity to platinum-based chemotherapy would increase the efficacy of personalized cancer treatment. The NER pathway promotes the repair for platinum-induced DNA damage , and genERCC5 rs17655 polymorphism showed no association with sensitivity to platinum-based chemotherapy. For the rs1047768 polymorphism, the C allele was associated with a significantly higher platinum sensitivity in both subgroups classified by cancer types. When stratified according to chemotherapy response evaluation criteria, the association in the RECIST subgroup was present only in the recessive model. However, large discrepancies existed between these two subgroups in the other three genetic comparison models. The stratified analysis by country revealed that significant association in the Chinese population, but not the other countries. Although we cannot exclude that we observed this difference due to the variation of genetic background among different ethnicities, it is also possible that the limited number for involved studies and samples from other nations led to this inconsistency.Stratified analyses based on cancer type, country, and chemotherapy response evaluation criteria were employed to detect subgroup difference. All subgroup results for the The source of heterogeneity in any meta-analysis should be comprehensively investigated to avoid possible distortion. Heterogeneity was detected in the recessive model of the rs1047768 polymorphism. To screen out the source of heterogeneity, subgroup analyses according to different factors were conducted. When stratifying according to cancer type, neither the NSCLC nor non-NSCLC subgroup exhibited heterogeneity. This indicated that cancer type accompanied by different pathogenesis and some other underlying drug response mechanisms might be the confounding factor which account for the heterogeneity in this comparison.Our meta-analysis had the following limitations. Other polymorphisms can influence ERCC5 mRNA or protein production  –31, and The entire study workflow strictly adhered to the instructions of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement . The robThe official name or alias for the ERCC5 gene , the terms for cancer , and the keywords standing for single nucleotide polymorphism  were utilized to form a boolean expression. This expression was systematically queried in Cochrane Library, Web of Science, and PubMed to collect potentially related studies published in English. All searches in these databases were finalized September 21, 2016.To identify the possibly relevant studies published in Chinese, the same boolean expression was then used in the China National Knowledge Infrastructure (CNKI) database. Additional search queries for chemotherapy  were used to filter the resulting publications. The Chinese literature search was finalized October 4, 2016.ERCC5 polymorphisms (rs1047768 and rs17655), and the sensitivity to the platinum-based chemotherapy for cancers; (3) genotype frequency data available was sufficient to build at least one genetic comparison model; (4) all values relating to ERCC5 polymorphism genotype frequencies were correct and not contradictory; (5) contained definitive chemotherapy response criteria. When two or more publications shared the same case and control samples, only the earliest study was included. Relevant publications without available data, even after email requests to their first/corresponding authors, were excluded. Four investigators participated in the selection, and another reviewer did a comprehensive inspection of the included studies.All included studies met the following selection criteria: (1) from peer-reviewed journals published in English or Chinese language; (2) unrelated case-control studies evaluating the association between the ERCC5 rs1047768 and rs17655 polymorphisms, and tumor response criteria were extracted from the identified studies by four investigators. Studies were re-checked to further confirm that they evaluated the association between the ERCC5 rs1047768 and rs17655 polymorphisms and the sensitivity to platinum-based therapies.Information including first author’s family name, year of publication, country, cancer type, genotype frequencies for the All statistics analyses in this meta-analysis were fulfilled using Review Manager software .ERCC5 rs1047768 and rs17655 polymorphisms from all included studies were tested using the homozygote , heterozygote , dominant , and recessive  genetic models. The ORs with 95% CIs were calculated to measure the association between these ERCC5 polymorphisms and platinum-based chemotherapy sensitivity. Heterogeneity was evaluated to make the choice between the random-effect  [P < 0.10), the random-effect model was applied. Otherwise, fixed-effect model was used.The extracted data for both the gorithm)  and the gorithm)  models. To evaluate the differences among subgroups, stratified comparisons between cancer types (NSCLC or others), countries (China or others), and chemotherapy response criteria (RECIST or others) were conducted. Publication bias was visually assessed via the funnel plot generated by Review Manager. To ensure stability of the results, the one-by-one sensitivity analysis with replacement was used to recalculate the ORs and 95% CIs on the remaining studies.ERCC5 rs1047768 polymorphism are more sensitive to platinum-based chemotherapy, especially for Chinese patients. However, the ERCC5 rs17655 polymorphism is not associated with sensitivity to platinating agents.Our meta-analysis showed that C allele carriers of the


STH) Q7R polymorphism has been reported to influence the individual's susceptibility to Alzheimer's disease (AD); however, conclusions remain controversial. Therefore, we performed this meta‐analysis to explore the association between STH Q7R polymorphism and AD risk. Systematic literature searches were performed in the PubMed, Embase, Cochrane Library and Web of Science for studies published before 31 August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association using a fixed‐ or random‐effects model. Subgroup analyses, Galbraith plot and sensitivity analyses were also performed. All statistical analyses were performed with STATA Version 12.0. A total of 19 case–control studies from 17 publications with 4387 cases and 3972 controls were included in our meta‐analysis. The results showed that the Q7R polymorphism was significantly associated with an increased risk of AD in a recessive model . After excluding the four studies not carried out in caucasians, the overall association was unchanged in all comparison models. Further subgroup analyses stratified by the time of AD onset, and the quality of included studies provided statistical evidence of significant increased risk of AD in RR versus QQ+QR model only in late‐onset subjects  and in studies with high quality . This meta‐analysis suggests that the RR genotype in saitohin Q7R polymorphism may be a human‐specific risk factor for AD, especially among late‐onset AD subjects and caucasian populations.Saitohin ( AD, the most common type of dementia in ageing population, is characterized by progressive cognitive impairment and memory loss. Extracellular amyloid plaques and intracellular neurofibrillary tangles are two core pathological hallmarks of AD et al. (2002) first reported that the RR genotype and R allele were associated with a higher risk for late‐onset Alzheimer's disease (LOAD) independently from APOE‐4 genotype  STH, an intronless gene, was first discovered between exons 9 and 10 of the human microtubule‐associated protein tau (MAPT) gene on chromosome 17q21.1 and rediscovered in MAPT 5′ intron 11 et al., Oliveira et al., and Clark et al., in 2003 The issue has been discussed in one meta‐analysis published in 2004 This meta‐analysis was performed according to the methodology advocated by the Meta‐analysis of Observational Studies in Epidemiology (MOOSE) guideline i) studies designed as case–control type; (ii) writing in English; (iii) reporting the association between STH Q7R polymorphism and AD and (iv) providing detailed genotype counts essential for the calculation of ORs and 95% confidence intervals (CIs). Exclusion criteria were as follows: (i) study design based on family or sibling pairs; (ii) case reports, editorials, reviews and meta‐analyses and (iii) insufficient information for data extraction. Additionally, if there was more than one publication from the same population, only the most recent or comprehensive study was included in the meta‐analysis.All studies eligible for the meta‐analysis had to meet the following inclusion criteria: . With regard to different results, a third reviewer participated in the discussion to solve the discrepancies.The following information was extracted and tabulated by two independent reviewers: the first author's name, year of publication, country of origin, ethnicity, total number of cases and controls, mean age of cases and controls, gender proportion of cases and controls, diagnostic criteria of AD, time of AD onset, genotype and allele distributions of cases and controls, and et al. (2005), which contains the representativeness of cases, representativeness of controls, ascertainment of cases, control selection, genotyping examination, HWE in controls and total sample size The quality of the studies included in the meta‐analysis was evaluated by a set of predetermined criteria by Thakkinstian et al. 05, whichversus Q), dominant model (RR+QR versus QQ), recessive model (RR versus QQ+QR), homozygous model (RR versus QQ) and heterozygous model (QR versus QQ). Subgroup analyses were also performed to evaluate the effect of Q7R polymorphism on AD susceptibility according to the differences in time of AD onset (EOAD or LOAD) and quality score of included articles , respectively. Statistical heterogeneity between studies was tested by I2 statistics and Q test. With the absence of heterogeneity (I2 < 50% or PQ ≥ 0.1), the pooled ORs were merged by the fixed‐effects model (the Mantel–Haenszel method), while with the presence of heterogeneity (I2 ≥ 50% or PQ < 0.1), the random‐effects model (the Der Simonian and Laird method) was used. If heterogeneity was detected, Galbraith plot analyses were conducted to find out whether there were outliers that could be the potential sources of heterogeneity. The HWE was assessed by chi‐squared test using genotype data from controls. A sensitivity analysis for the overall effect was conducted by sequential removal of the four studies in which the HWE in the control group was not reported, as they may generate possible bias P < 0.05 indicated a significant publication bias). All statistical analyses were performed with STATA Version 12.0 .Pooled ORs and 95% CIs were calculated to assess the association between STH Q7R polymorphism and the risk of AD under different comparison models, including allele model (R P > 0.05) A total of 126 articles were identified in the literature search of PubMed, Embase, Cochrane Library and Web of Science using different combinations of keywords , while a null result was reported in studies with low quality in all genetic models  was the outlier and main contributor to heterogeneity in R versus Q model . After excluding the four studies not conducted in caucasians versus Q model  and RR+QR versus QQ model ]  study was the outlier. Conrad et al.'s (2002) study was first to report the association between Q7R polymorphism and AD risk with 51 cases and 30 controls. Due to the small number of subjects, result from this study was not convincing and may have potential bias. Furthermore, subgroup analyses were performed to explore the sources of heterogeneity and the stability of the result. Age is a very important factor for AD development, and most of AD is diagnosed in people over 65 years. Results from the stratification by the time of AD onset showed that AD risk was associated with late onset in recessive model, which indicated that the STH Q7R polymorphism may be age‐dependently associated with AD susceptibility. Possible explanation for the age‐dependent association could be the difference in circulating C‐reactive protein (CRP) level, a well‐known inflammatory biomarker involved in the pathogenesis of AD Between‐study heterogeneity is very common in meta‐analyses for genetic association studies, and it is necessary to find out the potential sources. Our meta‐analysis also showed significant heterogeneity in allele model in the overall effects. Galbraith plot analysis indicated that Conrad The association of STH gene polymorphism with AD risk has been evaluated by a previous meta‐analysis with six studies included et al. (2005), the influence of language bias on meta‐analyses of observational studies may be as large as or even larger than its influence on randomized evidence To our knowledge, STH is an evolutionary locus that separates humans and their closest relatives from other mammals. The Q allele is remarkably common in humans; however, all nonhuman primates are homozygous for the R allele, which makes the Q allele a human‐specific marker and can be inferred to be most implicated in Alzheimer pathogenesis In conclusion, our meta‐analysis suggests that the RR genotype of STH Q7R polymorphism may be associated with an increased risk for AD, especially in caucasian population, late‐onset AD subjects and studies with high quality. Considering the limitations mentioned above, further well‐designed epidemiological studies with larger sample size and structure–function relationships should be conducted to confirm our findings.The authors declare no conflict of interest.Shaohua Wang and Rong Huang contributed to study conception and design; Rong Huang and Sai Tian acquired the data; Rongrong Cai, Jie Sun, Wenqing Xia, Xue Dong and Yanjue Shen performed the analyses; Rong Huang wrote the first draft; and Shaohua Wang and Sai Tian revised it critically for important intellectual content. All authors approved the final version to be published.


XPC gene, Lys939Gln (rs2228001 A > C) and Ala499Val (rs2228000 C > T), have been investigated in various types of cancer. We genotyped these two polymorphisms in 1141 cases with histologically confirmed colorectal cancer (CRC) and 1173 healthy controls to explore their causative association with CRC susceptibility. Overall, no association was observed between these two variants and the risk of CRC. Our meta-analysis also confirmed a lack of overall association. Stratified analyses were performed by age, gender, smoking status, pack-year, drinking status, tumor sites, and Duke’s stages. We found that XPC Lys939Gln polymorphism was significantly associated with an increased CRC risk in subjects at 57 years of age or younger (adjusted odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.004–1.86, p = 0.047) and non-drinkers . Our results indicated that XPC Lys939Gln may be a low-penetrance CRC susceptibility polymorphism. Our findings warrant further validation.Xeroderma pigmentosum group C (XPC) is a key component of the nucleotide excision repair (NER) pathway. Dysfunctional XPC protein may impair NER-mediated DNA repair capacity and further lead to genomic instability and carcinogenesis. Two common nonsynonymous polymorphisms in the  DNA damage constantly occurs because of the exposure to endogenous and exogenous mutagens. There are several DNA repair mechanisms that extensively eliminate genetic errors to maintain genome integrity, including base excision repair, mismatch repair, double-strand break repair, and nucleotide excision repair (NER). Among these DNA repair pathways, NER is in charge of repairing bulky DNA lesions, such as pyrimidine dimers, UV-induced DNA damage, chemical adducts, and crosslinks ,2. ThereXPC gene may influence the function of the protein and an individual’s DNA repair capacity, and thereby affect genetic instability and modify individual predisposition to cancer. XPC is an important protein in the NER pathway; it enables DNA repair by complexing with RAD23 homolog B (RAD23B) to facilitate the recognition of DNA damage and the initiation of DNA repair ,5,6. TheXPC gene, located on chromosome 3p25, is highly polymorphic. To date, at least 102 single nucleotide polymorphisms (SNPs) have been reported in the coding region of this gene [XPC Lys939Gln (rs2228001 A > C) and Ala499Val (rs2228000 C > T) polymorphisms have been foci of interest for their potential function, as well as association with the risk of various types of cancer, including breast cancer, lung cancer, bladder cancer, and colorectal cancer (CRC) [The his gene . Of thesGln rs222001 A > Cer (CRC) . Howeverer (CRC)  and the p = 0.518) when compared by the matching factor, gender. However, cases were significantly older than controls (55.7 ± 13.7 vs. 45.2 ± 11.6). The percentage of ever smokers in cases (27.3%) was significantly lower than that in controls (43.6%). The pack-years also differed significantly between cases and controls. Moreover, there were significantly fewer drinkers in cases than in controls. In this study, 44.3% (505) of cases had colon cancer, while 55.7% (636) had rectal cancer. In terms of the clinical stage, 130 (11.4%), 363 (31.8%), 359 (31.5%), and 289 (25.3%) patients were diagnosed with Duke’s stage A, B, C, and D colorectal carcinoma, respectively.We analyzed in total 1141 CRC cases and 1173 healthy controls in the present study . There wp = 0.300 for rs2228001 A > C, and p = 0.095 for rs2228000 C > T). Overall, neither XPC Lys939Gln (rs2228001 A > C) nor Ala499Val (rs2228000 C > T) polymorphism was associated with the risk of CRC (XPC genotypes had similar cancer risk to those carrying two wild-type genotypes (adjusted odds ratio (OR) = 1.13, 95% confidence interval (CI) = 0.77–1.66, p = 0.524 for carriers of one risk genotype; adjusted OR = 1.03, 95% CI = 0.69–1.54, p = 0.884 for carriers of two risk genotypes) (Genotype frequency distributions of the two SNPs in controls were in agreement with the Hardy–Weinberg equilibrium (HWE) (k of CRC . We nextnotypes) .XPC rs2228001 A > C polymorphism was significantly associated with an increased CRC risk in subjects at 57 years of age and younger . A stratified analysis also revealed increased CRC risk associated with rs2228001 for never smokers ; however, the significance of the association disappeared after adjustment for age, gender, smoking and drinking status. Moreover, non-drinkers carrying rs2228001 AA/AC genotypes showed a significantly increased risk of CRC , which was likely to be due to chance. In term of tumor sites, XPC rs2228001 A > C did not seem to confer predisposition to either colon cancer or rectal cancer. XPC rs2228001 A > C polymorphism was not associated with Duke’s stage, either. Moreover, no significant association with CRC risk was found for the rs2228000 C > T polymorphism in the stratified analysis. We performed a stratified analysis by age, gender, smoking status, pack-year, drinking status, tumor sites, and Duke’s stages . A stratXPC polymorphisms have been frequently studied for their ability to modify CRC susceptibility. However, results remain open to more than one interpretation. We next carried out meta-analysis to further explore the association between these two polymorphisms and CRC risk by including eligible publications and our data  flow diagram). Overall, there were 12 publications consisting of 13 studies (6107 cases and 8207 controls) for the rs2228001 A > C polymorphism and five publications consisting of six eligible studies (3533 cases and 4860 controls) for the rs2228000 C > T polymorphism (The two morphism . After pmorphism . Similarmorphism .XPC polymorphisms (rs2228001 A > C and rs2228000 C > T) and the risk of CRC was evaluated in 1141 CRC cases and 1173 healthy controls enrolled from southern China. We found no statistical evidence of a significant association between these two polymorphisms and the risk of CRC. A combined analysis with these two polymorphisms suggested that subjects carrying one or two risk genotypes did not show increased CRC risk, when compared with non-carriers. Stratified analyses by age, gender, smoking status, pack-year, drinking status, tumor sites, and Duke’s stages demonstrated a significant association between the XPC rs2228001 variant allele and increased CRC risk in participants at 57 years of age or under, non-smokers, and non-drinkers. However, in the stratified analysis, age, smoking status, and drinking status had no effect on the association between the rs2228000 C > T polymorphism and the risk of CRC. The role of the XPC gene in carcinogenesis started to attract attention because of the observation that mutations in the DNA repair genes can cause the inherited disease xeroderma pigmentosum (XP). This disease is characterized by hypersensitivity to UV light due to impaired DNA repair capacity. XP patients have an approximately 1000-fold higher risk of developing multiple skin cancers [XPC gene, XPC rs2228001 A > C, rs2228000 C > T [XPC rs2228001 A > C polymorphism, an A-to-C transition in exon 15, leads to a substitution of glutamine for lysine in codon 939 (Lys939Gln), while rs2228000 C > T polymorphism is a C-to-T transition in exon 8, resulting in the replacement of alanine with valine in codon 499  [XPC rs2228001 A > C polymorphism is located in the domain interacting with TFIIH. Both biological and biochemical evidence showed that XPC rs2228001 A > C polymorphism could alter the DNA repair capacity [XPC polymorphism were shown to have a reduced capacity of repairing benzo(a)pyrene DNA adducts [The association between two common nonsynonymous  cancers . Upon re cancers . There aa499Val) . The XPCcapacity ,20. More adducts .XPC rs2228001 A > C polymorphism and the risk of CRC among Caucasians [XPC rs2228001 A > C polymorphism in CRC among Asians [XPC rs2228001 A > C polymorphism was significantly associated with increased CRC risk under the heterozygous  and dominant  genetic models. In contrast, Yue et al. [XPC rs2228001 A > C polymorphism as a CRC susceptibility variant in some subpopulations, including participants at 57 years of age and under, non-smokers, and non-drinkers, but these findings could lack causality. Taken together, these findings suggest that XPC rs2228001 A > C polymorphism may be a low-penetrance common polymorphism with a moderate effect on CRC susceptibility. Large, well-designed multicenter studies, with consideration of epidemiological characteristics and lifestyles, should be performed to clarify the role of XPC rs2228001 A > C polymorphism in CRC carcinogenesis.Our findings were in line with some previous studies. A number of case-control studies have been carried out to investigate the association between ucasians ,26,27,28ucasians ,26,27,28g Asians ,12,29,30XPC rs2228001 A > C polymorphism, relatively fewer studies have examined the association of the rs2228000 C > T polymorphism with CRC susceptibility [When compared with the tibility ,27,28,29tibility ,28,29. Itibility ,31. SincReplication study is the golden method for the validation of the genetic associations. We tested the association of interest in the study with a relatively large sample size. As a result, the statistical power was largely increased in comparison with previous studies and the results were convincing. In the present study, the statistical power to detect a significant finding in younger subjects, never smokers, and never drinkers was 77.2%, 65.4%, and 47.9%, respectively. While using our sample size, the statistical power to detect the OR of 1.20 was approximately 70% in a recessive genetic model. Therefore, this study was important in defining genetic susceptibility to CRC. Given that the genetic backgrounds of populations may vary depending on regions and ethnicities, findings from other regions and races may not be applicable to the southern Chinese population. This study was the first one to evaluate the association in the southern Chinese population. Moreover, single case-control studies often yield conflicting results, partially due to the relatively small sample sizes of each study and variations in samplings, ethnicities, genotyping methods, and study designs  among studies. To overcome these drawbacks, we also conducted a meta-analysis on the associations of interest by pooling all eligible studies and ours together. The meta-analysis results verified our findings from the current case-control study. XPC gene. More potentially functional polymorphisms in the XPC gene should be studied. Third, details on other risk factors, including lack of exercise, being overweight or obese, and high consumption of red meat, were not available for cases and controls, which prevented us from further investigating the effects of these parameters on the association. Fourth, the current study was a gender matched case-control study; age and other factors, such as smoking and drinking status, were not factored into the study design, which might lead to a selection bias. Fifth, an information collection bias might exist. For example, the cases had a lower percentage of individuals with a history of smoking or alcohol consumption than controls did in our current study. Sixth, 32.2% of the cases with colorectal cancer were 50 years of age or younger, which was a little higher than that (21.9%) in previous investigations performed in central China [XPC rs2228001 A > C polymorphism on the development of CRC and clarify the underlying mechanisms.However, several limitations of the studies were deserving of attention. First, the present study only had a moderate sample size. Especially, the sample size in the stratified analysis was even smaller and for this reason the statistical power might be limited. Second, we only analyzed two potentially functional polymorphisms in the XPC rs2228001 A > C and rs2228000 C > T polymorphisms with CRC risk in the southern Chinese population. Our findings should be interpreted cautiously and warrant further validation in prospective investigations.In conclusion, we did not find any predominant effects of the We recruited 1141 cases with histologically confirmed CRC between January 2000 and May 2010 in Sun Yat-sen University Cancer Center. Patients with primary cancer in sites other than the colon and rectum were removed from the final study. Moreover, 1173 healthy residents in the same region were randomly recruited as controls in the same period of time, and they were frequency-matched to cases on gender. All the participants were of the ethnic Han Chinese population from southern China and genetically unrelated. Potential participants were contacted to screen for eligibility and the written informed consent was signed by each of the study subjects. A self-administered questionnaire was employed to collect information from individuals during a personal interview by their attending doctors, including demographic characteristics (age and gender), lifestyle , and family history of cancer. A blood sample of approximately 5 mL was obtained from each subject at the end of the interview. Overall, more than 80% of cases and controls responded. This investigation was approved by the institutional review board of Sun Yat-sen University Cancer Center . Written informed consent was obtained from all patients.Genotyping procedures were described elsewhere ,34,35. B2χ test and the Student’s t test to compare categorical variables and continuous variables between cases and controls, respectively. A goodness-of-fit 2χ test was used to check the significant deviation of SNP genotype frequencies from HWE in the control subjects. An unconditional logistic regression analysis was conducted to calculate ORs and 95% CIs. An additional adjustment for age, gender, smoking and drinking status was made in the multivariate logistic regression analysis. We also carried out a stratified analysis by age, gender, pack-years, smoking and drinking status to study whether these factors could modify the association of interest. All analyses were performed using SAS software . All tests were two-sided. Results were considered statistically significant at p < 0.05.We performed Pearson’s Xerodermapigmentosum group C or XPC”, “Lys939Gln or rs2228001”, “Ala499Val or rs2228000”, “polymorphism or variant or variation”, and ‘‘colorectal cancer or tumor or carcinoma or neoplasm or CRC”. Literature searches were performed between October and November 2015. Detailed procedures referred to previous publications [Q-Test. The fixed-effects model (the Mantel–Haenszel method) [The meta-analyses were conducted on the association between the two SNPs (rs2228001 A > C and rs2228000 C > T) and CRC susceptibility following the PRISMA checklist . Systemaications ,38,39,40 method)  or the r method)  would be method) . Further


Dopaminergic and glutamatergic dysregulation are among the leading hypotheses for schizophrenia. Previous in vivo imaging studies have shown that increased striatal presynaptic dopamine synthesis capacity (DSC) predates the onset of psychosis and is associated with symptom severity. Recent meta-analysis in magnetic resonance spectroscopy studies in schizophrenia reported increased levels of glutamate and glutamine (Glx) in basal ganglia and medial frontal cortex in clinical high-risk groups for psychosis. Despite the evidence of alterations in both dopamine and glutamate in schizophrenia, the degree to which these alterations are trait markers linked to genetic risk for psychosis or reflects state changes is not clear from previous studies. Over the last fifteen years, it has been well established that 22q11 deletion is one of the most important genetic risk factors for the development of schizophrenia. Individuals with 22q11 deletion are at increased genetic risk for psychosis, reaching a prevalence 30% for psychotic disorder. The aims of our study were to investigate dopaminergic and glutamatergic function in individuals with 22q11.2 deletion.Participants underwent 18F DOPA PET, MRI, as well as clinical measures.21 individuals with 22q11 deletion : 26.1(7.72)) and 26 healthy volunteers : 26.12(4.28)) took part in the 18F DOPA PET. Standardised ROIs was defined in the striatum, including limbic, associative and sensorimotor sub-regions, and the reference region, defined according to previous study. The ROI atlas was normalised to each individual PET dynamic image. A Patlak analysis was applied to calculate influx constants  for the whole striatal ROI relative to uptake in the cerebellar reference region (Kicer [min-1]).In addition, 17 individuals with 22q11 deletion : 26.39(7.7)) and 30 healthy controls : 27.17(4.8)) had MRI. 1H-MRS voxels were placed on the anterior cingulate cortex and left striatum. Spectra were analyzed using LC Model version 6.3-1L. Poorly fitted metabolite peaks (Cramer–Rao minimum variance bounds >20% as reported by LC Model) were excluded from further analysis.DSC in the whole striatum was significantly increased in the individuals with 22q11 deletion compared to healthy controls . In addition, no difference was found between groups in Glx levels in anterior cingulate cortex  and left striatum (t(44) =-1.065; p=0.29, t(42)=-0.172;p=0.86, respectively).Psychopathology scales were not correlated with either dopaminergic or glutamatergic function in the group of 22q11 deletion.Our findings provide evidence that dopamine synthesis capacity has a strong trait component and glutamatergic dysfunction may be most likely associated with disease status. Future studies with longitudinal design are warranted to further investigate the role of dopamine and glutamate in individuals with 22q11 deletion. Moreover, there is a clear need for studies utilizing higher field resonance strength and appropriate radiotracers to investigate glutamatergic function in this population. These will be crucial steps towards the development of new treatments, that can be applied in early stages of illness.


TERT, rs2736100 C/A, is associated with both telomere length and multiple diseases. Carriage of the C allele is associated with longer telomere length, while carriage of the A allele is associated with shorter telomere length. Furthermore, some diseases have a positive association with the C and some with the A allele. In this study, meta-analyses were performed for two groups of diseases, cancerous diseases, e.g., lung cancer and non-cancerous diseases, e.g., pulmonary fibrosis, using data from genome-wide association studies and case-control studies. In the meta-analysis it was found that cancer positively associated with the C allele (pooled OR 1.16 [95% CI 1.09–1.23]) and non-cancerous diseases negatively associated with the C allele (pooled OR 0.81 [95% CI 0.65–0.99]). This observation illustrates that the ambiguous role of telomere maintenance in disease hinges, at least in part, on a single locus in telomerase genes. The dual role of this single nucleotide polymorphism also emphasizes that therapeutic agents aimed at influencing telomere maintenance should be used with caution.The enzyme telomerase reverse transcriptase (TERT) is essential for telomere maintenance. In replicating cells, maintenance of telomere length is important for the preservation of vital genetic information and prevention of genomic instability. A common genetic variant in  TERT), and a RNA template, encoded by telomerase RNA component.Telomere biology is emerging as a significant factor in an increasing number of diseases –4. StudiTERT gene has been reported in the context of several cancer types  –16. Theser types –20. Theser types . Telomerer types , 22.However, Telomere biology is an ambiguous factor in cancer pathology –25. In hTERT gene (5p15.33). Interestingly, the first report on a disease association to this SNP, was to the non-cancerous disease IPF  rs2736100 in the ease IPF . An IPF ease IPF . Later sease IPF , 42. ThiTERT SNP rs2736100 and to gain insight in the balancing act between telomere maintenance and disease predisposition.The aim of this study is to conduct a systematic review and meta-analysis of disease association studies with TERT SNP rs2736100 by using “rs2736100” as search input , and OR and 95% confidence interval (95% CI). Furthermore, the used inheritance model was checked as well as in which allele specifically was associated with the studied disease. When this information was not provided it was derived from the provided genotype data when possible.(Publication) bias was evaluated by visual inspection of Doi plots, as well as calculates the Luis Furuya-Kanamori (LFK) index, which provides a statistic for the amount of bias in a Doi plot .rs2736100 associations and (publication) bias were both analyzed using meta-analysis software MetaXL 4.0 . Due to the large number of different diseases that were included in this study, a high level of variation in study outcome, heterogeneity, was expected. The meta-analysis was, therefore, performed using the inverse variance heterogeneity method, to determine the pooled result and heterogeneity . Many stTERT SNP rs2736100 with a group of cancer diseases and with a group of non-cancerous diseases. Table A meta-analysis was performed to analyze the association of n = 46) involved studies on lung cancer (n = 33) and glioma (n = 13). The majority of studies reported a positive association with the C allele of rs2736100. However, four of the included studies reported a negative association with the C allele, these included two studies on testicular cancer, one on colorectal cancer and one on pancreatic cancer  bias was evaluated for both the cancer and non-cancer study Figure . For botThe ambiguous effects of telomere maintenance do pose a great challenge for the development of therapeutic agents, for instance putative anti-aging therapeutics. Therapeutic agents aimed at increasing telomere length should be used with caution , 134. TeTERT SNP rs2736100 C allele is positively associated with multiple cancerous diseases, while the A allele is positively associated with predisposition to non-cancerous (degenerative) diseases. Because the SNP is known for its influence on telomere length, this result illustrates that optimal telomere maintenance balances between increasing the risk for cancer or for non-cancerous diseases. This underlines the caution that should be taken when developing therapies that influence telomere length.Meta-analyses showed that the RS and CM contributed to the study concept and design, data analysis and interpretation, writing of the manuscript and final approval; had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. MO and JG contributed to the study concept and design, writing of the manuscript and final approval; had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


ADAM12) gene polymorphisms and knee osteoarthritis (KOA) have given controversial and indefinite results. Therefore, we performed a meta-analysis to confirm this correlation. We searched the PubMed, Embase, and SinoMed databases for all papers published up to April 11, 2017. Overall, five different studies, totaling 2,353 cases and 3,668 controls, were retrieved on the basis of the search criteria for KOA susceptibility related to four polymorphisms  in the ADAM12 gene. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed using Egger's and Begg's tests. The rs3740199 G/C polymorphism was found to be associated with increased KOA risk in men , but not in the overall analysis and in analyses of other subgroups. Significantly increased associations were also found for the rs1871054 polymorphism . However, there were no associations for the rs1278279 and rs1044122 polymorphisms. Furthermore, no obvious evidence of publication bias was detected. Our study indicated that the rs1871054 polymorphism of ADAM12 was significantly associated with increased KOA risk.Previous studies that evaluated the association between a disintegrin and metalloprotease 12 ( PRKAR2B), HMG-box transcription factor 1 (HPB1), component of oligomeric Golgi complex 5 (COG5), G protein-coupled receptor 22 (GPR22), growth differentiation factor 5 (GDF5), and a disintegrin and metalloprotease 12 (ADAM12) [Osteoarthritis (OA) is a common late-onset degenerative joint disease affecting millions of people worldwide. The prominent features of OA include progressive degradation of articular cartilage, accompanied by joint space narrowing, subchondral bone sclerosis, and osteophyte formation at the joint margin; these symptoms result in chronic joint pain and restricted motion . Little (ADAM12) , 5, are ADAM genes, ADAM12 is a candidate gene in the etiology of OA. The cellular roles of ADAM12 appear to be critical in both normal physiology and pathology. Several studies have suggested regulatory roles of human ADAM12 in bone formation, chondrocyte proliferation and maturation, and osteoclast differentiation [ADAM12 gene have previously been shown to be associated with KOA [ADAM proteins, members of the Zn-dependent metzincin superfamily, have been shown to be associated with several complex diseases, such as rheumatoid arthritis, heart disease, Alzheimer's disease, and cancer , 7. Amonntiation –11. Morentiation . A previntiation . Importawith KOA –20.ADAM12 gene polymorphisms  with KOA susceptibility.Considering the critical role of ADAM12 in KOA, we performed a meta-analysis of all eligible case-control studies to obtain a more accurate picture of the association of four ADAM12 with the risk of KOA  that evaluated the association of the rs3740199, rs1278279, rs1871054, and rs1044122 polymorphisms in Pheterogeneity = 0.538, P = 0.726, fixed model, Figure Pheterogeneity = 0.527, P = 0.758, fixed model), and the dominant model , homozygote comparison  and is applied only one model at a time. However, the bias of this method has been pointed out by a previous study [Our analysis used Chi-squared and us study . Therefoz = 0.73 and P = 0.462 for Begg's test, and t = -0.08 and P = 0.944 for Egger's test . No proof of publication bias was obtained. For example, in the additive model analysis (CC+CG versus GG), we obtained values of Identification of gene polymorphisms related to OA susceptibility could not only make it possible to predict the disease phenotypes and construct OA prediction models based on genotype information , but alsADAM12 gene have been reported to be associated with KOA development and progression [Polymorphisms in the gression , 18, 25.gression , 26. Sucgression . LimitedADAM12 gene with KOA susceptibility. In the overall analysis of 2,354 KOA cases and 3,668 controls, only the rs1871054 polymorphism was found to be associated with KOA risk, and individuals carrying the C allele may have a high susceptibility for the condition. Furthermore, in the sex-stratified analysis, although there was an increased association between the rs3740199 polymorphism and KOA risk in individuals carrying the CC and CG genotypes, this polymorphism site was not associated with KOA risk in the whole and subgroup analyses after using the genetic model-adjusted P value [To the best of our knowledge, this is the first meta-analysis to evaluate the association of common polymorphisms in the  P value . It is pADAM12 gene expression in serum from peripheral blood, disease stage, and lifestyle. Despite the above drawbacks, our meta-analysis had three advantages: a substantial number of cases and controls were pooled from different studies, which increased the statistical power of the analysis significantly; the quality of the case-control studies included was satisfactory based on our selection criteria; and publication bias was not detected in all genetic models, suggesting that the results were relatively stable and powerful.Meta-analysis is a recognized effective method for addressing a variety of clinical questions by summarizing and reviewing published quantitative studies. However, some limitations in our meta-analysis should be mentioned. First, the number of included studies was not large enough for a comprehensive analysis, although we identified all available studies. Second, KOA risk may be modulated by gene-gene and gene-environment interactions, as well as those among different polymorphic loci in the same gene, which should be considered in further research. Third, most of the included studies were hospital-based, which may lead to lack of representation. Moreover, except for one study, all the other included studies were from Asia, which resulted in a limitation of ethnicity representation. Fourth, our meta-analysis was based on unadjusted estimates. A more precise analysis could be conducted if individual data were available, to allow for adjustment by other covariates, including age, family history, environmental factors, ADAM12 gene and increased KOA risk. More well-designed, large-scale studies focusing on gene-gene and gene-environment interactions are warranted to improve our understanding of the correlation between ADAM12 gene polymorphisms and the risk of KOA development.In summary, our present meta-analysis showed evidence of significant associations between the rs1871054 polymorphism in the We conducted searches on the PubMed, Embase, and SinoMed databases, with the last search updated on April 11, 2017. The keywords used were “ADAM12” or “a disintegrin and metalloprotease 12,” “polymorphism” or “variant,” and “osteoarthritis” , withoutADAM12 gene, (ii) case-control studies, and (iii) sufficient genotype numbers  in both cases and controls. The following exclusion criteria were used: (i) no control population, (ii) no available number in genotyping frequency, and (iii) duplication of previous publications.Studies that were included in our analysis had to meet all of the following criteria: (i) published studies according to the correlation between KOA and rs3740199/rs1278279/rs1871054/rs1044122 polymorphisms in the The Newcastle-Ottawa Scale (NOS)  was seleTwo of the authors independently extracted all data and ensured that they complied with the selection criteria. The following information was obtained: first author's last name, year of publication, country of origin, ethnicity, total and each genotype number in case/control group, source of controls, HWE of controls, sex data, and genotyping methods. Ethnicity was categorized as Caucasian or Asian. The control subgroups were population-based and hospital-based, and the sex subgroup was classified by male and femaleADAM12 gene and KOA. Fixed effects and random effects models were used to calculate pooled ORs. The statistical significance of the total OR was determined using Z-tests. Heterogeneity assumption was performed using a χ2-based Q-test among the studies. If the P value was greater than 0.10 for the Q-test, indicating a lack of heterogeneity among the studies, the fixed effects model (Mantel-Haenszel method) was chosen; otherwise, the random effects model (DerSimonian-Laird method) was used [ADAM12 gene polymorphisms, we investigated the association between genetic variants and KOA risk based on allelic contrast , heterozygote comparison , homozygote comparison , the recessive genetic model , and the dominant genetic model . A sensitivity analysis was performed by omitting studies, one after the other, to assess the stability of results. Departure of the frequencies of the ADAM12 gene polymorphisms from HWE was assessed by Pearson's χ2 test, where results of P < 0.05 were considered significant [P < 0.05 were considered significant [http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize#Windows).ORs with 95% CIs were used to measure the strength of associations between polymorphisms in the was used , 29. Fornificant . Publicanificant . All staADAM12 gene was conducted using methods described in the retrieved literature; namely, polymerase chain reaction with restriction fragment length polymorphism; polymerase chain reaction with high-resolution melting; and improved multiplex ligase detection reaction.Genotyping of the polymorphisms in the


MTHFR C677T, MTHFR A1298C, Prothrombin G20210A, FVLG1691A, and PAI-1 4G/5G) and RPL risk in the Iranian population. PubMed, Web of Science, Google Scholar, and ISC were searched for eligible articles published up to April 1, 2017. In total, 37 case-control studies in 18 relevant publications were selected: 1,199, 1,194, 630, 830, and 955 RPL cases and 1,079, 1079, 594, 794, and 499 controls for MTHFR C677T, MTHFR A1298C,Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G, respectively. The results indicated a significant increased risk of RPL in all genetic models in the population. Also, Prothrombin G20210A and FVL G1691A as well as PAI-1 4G/5G polymorphisms were associated with RPL risk in the Iranian population. Hence, thrombophilic genes polymorphisms are associated with an increased RPL risk in the Iranian population.Studies have indicated that thrombophilic genes polymorphisms are associated with recurrent pregnancy loss (RPL) in the Iranian population. We aimed to evaluate the precise association between thrombophilic genes polymorphisms ( The miscarriage of three or more consecutive pregnancies in the first or early second trimester is termed as recurrent pregnancy loss (RPL). SeveralFVL), Prothrombin G20210A (PTG20210A), and Methylene tetrahydrofolate reductase (MTHFR) C677T are candidate genes for venous thromboembolism (VTE)[MTHFR C677T, MTHFR A1298C, Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G in RPL[MTHFR C677T, MTHFR A1298C, Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G) and RPL risk in the Iranian population.Three common inherited thrombophilia markers, namely Factor V Leiden (ism (VTE). Various5G in RPL. HoweverMTHFR C677T, MTHFR A1298C, Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G polymorphisms and RPL risk in the Iranian population. The following key terms were included in our search: “recurrent pregnancy loss”, ‘’recurrent miscarriage’’, ‘’habitual abortion’’, “RPL”, “thrombophilic gene”, “MTHFRC677T’’, “MTHFR A1298C’’, “Prothrombin G20210A’’, “Factor V Leiden G1691A’’, “PAI-1 4G/5G’’, “polymorphism”, “variant”, “gene”, “genotype”, “SNP”, and “allele”. The extracted publications were limited to Persian and English languages and conducted only on human subjects. We retrieved those publications matching the keywords without no restriction, and then the studies were evaluated by reading the title and abstract. We have also screened the reference lists of the retrieved articles for original papers. If there were multiple reports of the same study or overlapping data, only the study with the largest sample sizes or the most recent one was selected in our meta-analysis, and the others were excluded.To identify eligible studies for this meta-analysis, we searched the PubMed, Web of Science, Google Scholar databases, ISC, and EMBASE. In the search, we considered all eligible articles published up to April 1, 2017 that examined the association between the MTHFR C677T, MTHFR A1298C, Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G polymorphisms and the risk of RPL in the Iranian populations, (4) offered the size of the sample and sufficient data (genotype distributions of both cases and controls were available) for estimating OR with 95% CI, and (5) written in English or Persian. The exclusion criteria were as follows: (1) abstracts, case reports, letter to the editor, and reviews, (2) studies with only case group (no control population), (3) studies on other poly-morphisms of thrombophilic genes, (4) studies without detail genotype frequencies in which calculation of OR is impossible, and (5) duplicate publications of data from the same study.The included studies to the meta-analysis had to be consistent with the following criteria: (1) published in full-text, (2) be case-control or cohort design, 3) evaluate the association between Two investigators independently extracted the data using a pre-designed form. Based on the inclusion and exclusion criteria, we extracted the following data from each study: the first author, year of publication, number of RPL patients and controls, genotype and allele frequency, minor allele frequencies (MAFs) in control subjects, and Hardy-Weinberg equilibrium (HWE) test in control subjects. For conflicting evaluation, these two investigators carried out discussions until a consensus was reached.P values were two-tailed with a significant level at 0.05. The strength of associations was assessed by using ORs and 95% CIs, and the significance of pooled ORs was examined by Ztest. We performed a meta-analysis of the association between MTHFR C677T polymorphism and RPL under the allelic model (T vs. C), the homozygote model (TT vs. CC), the heterozygote model (CT vs. CC), the dominant model (TT + CT vs. CC), and the recessive model (TT vs. CT + CC). The MTHFR A1298C polymorphism was evaluated using the allelic model (C vs. A), the heterozygote model (AC vs. AA), the homozygote model (CC vs. AA), the dominant model (CC + AC vs. AA), and the recessive model (CC vs. AC + AA). The Prothrombin G20210A and FVL G1619A polymorphisms were assessed under the allelic model (A vs. G), heterozygote model (GA vs. GG), the homozygote model (AA vs. GG), the dominant model (AA + AG vs. GG), and the recessive model (AA vs. AG + GG). PAI-1 4G/5G polymorphism was assessed under the allelic model (4G vs. 5G), the heterozygote model (4G/5G vs. 5G/5G), the homozygote (4G/4G vs. 5G/5G), the dominant model (4G/4G + 4G/5G vs. 5G/5G), and the recessive model (4G/4G vs. 4G/5G + 5G/5G). Heterogeneity assumption was checked by a chi-square-based Q-test, and I2 statistics was calculated to quantify the proportion of the total variation across studies due to heterogeneity[p < 0.1 or I2 > 50%. An I2 value of 0% represents no heterogeneity, and with the values of 25%, 50%, 75%, or more, it represents low, moderate, high, and extreme heterogeneity, respectively. A P value greater than 0.10 indicated the lack of heterogeneity among studies; therefore, the fixed-effects model (Mantel-Haenszel method) was used to calculate pooled OR[p < 0.01 signified a departure from HWE[p < 0.05 was considered statistically significant[All the statistical analyses were performed by comprehensive meta-analysis (CMA) version 2.0 software . All rogeneity. The hetpooled OR. Otherwi from HWE. One-way from HWE. Publicagnificant. SensitiMTHFR, Prothrombin, FVL, and PAI-1 genes. As summarized in Tables MTHFR C677T (from ten studies), 1,194 RPL cases and 1079 controls for MTHFR A1298C (from ten studies), 630 RPL cases and 594 controls for Prothrombin G20210A (from five studies), 830 RPL cases and 794 controls for FVL G1691A (from seven studies), and 955 RPL cases and 499 controls for PAI-1 4G/5G (from five studies). Genotype distributions in the controls of ten case-control studies were not in agreement with HWE.Based on the search criteria, 53 individual literatures were found. After screening the titles and abstracts, 35 publications that did not meet the criteria were excluded. These studies were reviews, short reports, case reports, and other polymorphisms of MTHFR C677T and A1298C polymorphisms and RPL risk in the Iranian population. When all the eligible studies were pooled into the meta-analysis of MTHFR C677T polymorphism, a significant increased risk of RPL was observed in the allelic model , the heterozygote model , the homozygote model , the dominant model . In addition, when all the eligible studies were pooled into the meta-analysis of MTHFR A1298C polymorphism, a significant association was observed in the allelic model , the heterozygote model , the homozygote model , and the recessive model .Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G polymorphisms with RPL risk in the Iranian population. Among the eligible studies were pooled to the meta-analysis of Prothrombin G20210A polymorphism, only allelic and dominant model was applicable because they provided the genotypes of AA + GA vs. GG. Therefore, the pooled analyses showed a significant association between Prothrombin G20210A polymorphism and RPL in the Iranian population in the allelic model . When all the eligible studies were pooled into the meta-analysis of FVL G1691A polymorphism, we observed a significant increased risk of RPL under allelic model , but not in the heterozygote model , the homozygote , and the recessive model . In addition, there was a significant association between PAI-1 4G/5G polymorphism and RPL in thep < 0.001), the homozygote model , the dominant model , but not in the heterozygote model .Iranian population in the allelic model .MTHFR A1298C, Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G, and this result was confirmed by Begg’s test and Egger’s test , but not for MTHFRC677T . Therefore, we used the Duval and Tweedie non-parametric “trim-and-fill” method to adjust the results of publication bias for MTHFR A1298C polymorphism recessive model. However, the meta-analysis with and without ‘‘trim-and-fill’’ method did not show different results, showing that the results of this meta-analysis are statistically robust.In this meta-analysis, Begg’s funnel plot and Egger’s test were used to assess the publication bias of included studies. The funnel plot revealed no obvious publication bias for r’s test . Howeverve model , suggestMTHFR C677T or A1298C polymorphisms were found to contribute to the etiology of RPL in different populations[MTHFR A1298C poly-morphism may not responsible for increased total homocysteine, it seems that this polymorphism contributes significantly to the increased homocysteine levels[MTHFR C677T polymorphism is significantly associated with the increased risk of RPL. For instance, Chen et al.[MTHFR C677T was significantly associated with RPL risk in the Chinese population under all genetics models. Similarly, Wu et al.[et al.[MTHFR C677T polymorphism was associated with the increased risk of RPL among Asians, but not Caucasians. Based on these studies, the MTHFR 677TT polymorphism has a significant increased likelihood of RPL in Asians, which is in agreement with our conclusion. The data of a meta-analysis by Nair et al.[MTHFR A1298C polymorphism was a genetic risk factor for RPL. However, Cao et al.[MTHFR A1298C polymorphism and RPL susceptibility. The combined data, based on previous studies, showed that both MTHFR C677T and MTHFR A1298C polymorphisms might be a risk factor for RPL.It is known that folate is required for the proper development of fetus and placenta. Aberratpulations. Althougne levels,35. Preven et al. in a metWu et al. and Cao l.[et al. findingsir et al. showed tao et al. did not Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G with the risk of RPL, which were consistent with the majority but not all previous studies[et al.[Prothrombin G20210A variant was reported to increase the risk of RPL [et al.[FVL G1691A or Prothrombin gene polymorphisms were associated with the increased risk of two or more miscarriages compared with women without these polymorphisms. In addition, in three meta-analyses, Chen et al.[et al.[et al.[PAI-1 4G/5G polymorphism might be associated with RPL development.As for the other two polymorphisms, we also find a significant association of polymorphisms in s studies-42. In aes[et al., the Prodary RPL), particuL)[et al. found then et al., Su et al.[et al. and Li el.[et al. suggesteBetween-study heterogeneity, a multifactorial phoneme in meta-analyses, is a potential problem when interpreting the results-50. In aThere was an inevitable publication bias in our meta-analysis because we retrieved only published studies. Publication bias was assessed by funnel plots whose symmetries were further evaluated by Egger’s linear regression tests. We have suggested that for the recessive model, the publication bias might be owing to the limited number of the selected studies. Therefore, the negative results in our meta-analysis are possibly due to the limited number of publications to determine statistical significance.To the best of our knowledge, there is no earlier study on the analysis of thrombophilia gene polymorphisms in RPL in the Iranian population. However, in interpreting results of this meta-analysis, some limitations should be addressed. First, there was no sufficient number of relevant studies to explore more comprehensive association between the thrombophilic genes and RPL in the Iranian patients. Second, in this meta-analysis, only published studies were searched. It is possible that some important unpublished studies that meet our inclusion criteria were missed and ignored in the literature search. Therefore, inevitable publication bias might be exist, which could eventually help explain the possible existence of publication bias in the recessive model. Third, the Iranian population is mixed of different ethnicities, including Persian, Azeri, Kurdish, Lurs, Gilaki, Balochi, etc. However, we did not conduct subgroup analyses because insufficient data were available from the primary literature search. Moreover, due to limited individual data, a more precise analysis on other covariates, such as age, number of abortions, and environmental factors should be performed. As a result, more studies with large sample sizes in view of these factors are also desired. Finally, due to the lack of the original data, we did not take potential interactions among gene-gene , gene-environment, or even different polymorphism loci of the same gene, which all may affect RPL risk in the population.MTHFR C677T, MTHFR A1298C, Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G polymorphisms and RPL risk in the Iranian population. In addition, the direction of further research with a larger sample size should focus not only on the simple relationship of thrombophilic genes polymorphisms and RPL risk but also on gene-gene and gene-environment interactions.In conclusion, based on the available evidence, the current meta-analysis demonstrates that there is a significant association between the


MTHFR) C677T polymorphism and colorectal cancer (CRC) susceptibility has been researched in numerous studies. However, the results of these studies were controversial. Therefore, the objective of this meta-analysis was to offer a more convincible conclusion about such association with more included studies. Eligible studies published till May 1, 2017 were searched from PubMed, Embase, Web of Science, and CNKI database about such association. Pooled odds ratios (ORs) together with 95% confidence intervals (CIs) were calculated to evaluate such association. And the Begg’s funnel plot and Egger’s test were applied to assess the publication bias. This meta-analysis contained 37049 cases and 52444 controls from 87 publications with 91 eligible case–control studies. Because of lack of data for a particular genotype in several studies, all the included studies were analysed barely in the dominant model. Originally, there was no association between MTHFR C677T polymorphism and CRC susceptibility . After excluding 13 studies according to their heterogeneity and publication bias, rs1801133 polymorphism was found to reduce the risks of CRC significantly . In the subgroup analysis of ethnicity, there was a significant association in Asians . Furthermore, when stratified by the source of controls and genotyping methods, the positive results were observed in population-based control group  and PCR-restriction fragment length polymorphism (PCR-RFLP) method (OR =0.95, 95% CI =0.91–0.99. The results of the meta-analysis suggested that MTHFR C677T polymorphism was associated with CRC susceptibility, especially in Asian population.The association between methylenetetrahydrofolate reductase ( Escherichia coli infection [Colorectal cancer (CRC) is a critical public health problem, which is the third most commonly diagnosed cancer and the third common cause of cancer deaths in both males and females. There were 134490 new CRC cases and 49190 mortalities by estimation in the United States in 2016 [nfection . These s9, methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate [MTHFR not only plays a role in making proteins and other important compounds, but also is an important factor in DNA methylation, synthesis, and repair [MTHFR gene located on the short arm of chromosome 1-1p36.3 [MTHFR gene have been found and MTHFR C677T (rs1801133) is the most common type amongst them. MTHFR C677T represents an alanine-to-valine substitution at nucleotide position 677 in exon 4 resulting in thermolability and concurrent decreased activity of the enzyme [MTHFR gene mutations lead to MTHFR enzyme dificiency, low plasma folate levels, hyperhomocysteinemia [As a key enzyme and an important regulator for the metabolism of folate/vitamin Brofolate . Simultarofolate . Therefo77T rs18033 is thee enzyme . MTHFR g7T rs18013 is the teinemia  and certteinemia –21. WithMTHFR C677T polymorphism and CRC susceptibility. But, the results are still inconclusive so far. Thus, the aim of this meta-analysis including all available case–control studies was to investigate a more reliable association.Many researchers have carried out a large number of studies to examine the potential association between MTHFR C677T polymorphism and CRC susceptibility till May 1, 2017. The search strategy included listed key words: ‘methylenetetrahydrofolate reductase’, ‘MTHFR polymorphism’, ‘C677T’, ‘rs1801133’, and ‘risk or susceptibility’ and ‘colorectal or colon or rectal cancer’. Furthermore, we manually searched the reference lists of clinical trials and former meta-analyses for more relevant studies. When duplicate data appeared in different publications, this meta-analysis only adopted the most recent study or the study with the most complete information. The meta-analysis was on the basis of the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) [MTHFR C677T polymorphism and CRC susceptibility; (iv) offering enough raw data to calculate odds ratio (OR) with 95% confidence interval (CI). Additionally, exclusion criteria were as follows: (i) non-case–control studies; (ii) lack of sufficient data for calculating genotype frequency; (iii) case–control studies about examining the relationship between MTHFR C677T polymorphism and colorectal adenoma; (iv) duplicated publications.We searched several databases including PubMed, Embase, Web of Science, and CNKI database for published studies about exploring the association between RISMA-P) . The eliIn order to guarantee the accuracy of extracted information, two authors individually reviewed each publication and extracted useful data on the basis of the inclusion criteria listed above. When disagreements arose in the course of data extraction, discussion was carried out with other authors until the agreements were reached. The following information were extracted from each study to accomplish a standardized sheet: first author’s name, year of publication, ethnicity of population, source of controls , genotyping method, sample size of cases and controls, genotype frequency of rs1801133 in cases and controls, and the results of the Hardy–Weinberg equilibrium (HWE) test.MTHFR C677T polymorphism and CRC susceptibility was analyzed by using five models including the dominant model (CT + TT compared with CC), the recessive model (TT compared with CT + CC), the homozygous model (TT compared with CC), the heterozygous model (CT compared with CC), and the allele model (T compared with C). The goodness-of-fit χ2 test was conducted to evaluate the HWE in control groups and P<0.05 was regarded as significant disequilibrium [P<0.05, publication bias existed [The relationship between ilibrium . Stratifilibrium . Galbraiilibrium . A sensi existed . All staAccording to PRISMA-P, this meta-analysis contained 37049 cases and 52444 controls that were combined from 87 publications with 91 eligible case–control studies to examine the relationship between rs1801133 polymorphism and CRC risks –112. TheMTHFR C677T polymorphism and CRC susceptibility in the dominant model . 0.94–1.05). Nevertheless, for the sake of looking for possible reasons that might lead to such result, we performed heterogeneity analysis and tested publication bias. According to these results, 13 studies were excluded [P-value was estimated to be 0.824, and the fixed effect model was applied. Ultimately, the results demonstrated that the rs1801133 polymorphism was significantly correlated with the risk of CRC  genotype was closely linked to reduced incidence of CRC with low consumption of alcohol. In the next few years, similar results were replicated by several other studies [MTHFR CT heterozygote had a significantly increased risk of developing CRC and no increased cancer risk was observed in TT homozygotes [MTHFR C677T and the risks of CRC. Owing to the difference in study design and the sample size, the different ethnicity, and the diverse stratification, these controversial results were found in published studies. Hence, meta-analysis is essential to be carried out by combining all studies that meet the requirements to get more precise conclusions.Several polymorphisms have been reported about the n et al. , first r studies –111. Howozygotes . In addiozygotes  found noMTHFR C677T polymorphism and the susceptibility to CRC before [In recent years, there were several meta-analyses performed to elucidate the association of C before ,115–118.When stratified by ethnicity, there was a significant association with reduced risks of CRC in Asians. The result was consistent with the two previous meta-analysis based on the Asians ,117. ZhoIn the present meta-analysis, we had obtained weak associations significantly with a large sample size. However, the potential limitations of the meta-analysis should be acknowledged. First, this meta-analysis was based on unadjusted effect estimates and 95% CI, and the influence of multiple cofactors such as age, gender, diet habits including intake of alcohol and consumption of cigarette, the level of folate, and the other environmental factors should be taken into consideration. Second, because of incomplete data of some genotypes, only the dominant model was analyzed in all the included studies. Third, we did not perform stratification analysis by serum folate levels, locations of the tumor and so on, which might result in confounding bias. In addition, after excluding 13 studies according to the analysis of heterogeneity and publication bias, the heterogeneity decreased significantly and the publication bias seemed to disappear. However, the selection bias existed because all the studies were published. Furthermore, the gene–gene and gene–environment interactions were not mentioned in this meta-analysis. In addition, the potential roles of the gene polymorphism which were hidden or magnified by other interactions were omitted.MTHFR C677T polymorphism and susceptibility to CRC. Simultaneously, the TT genotype of MTHFR C677T polymorphism could reduce the risk of CRC. In addition, the associated risk of CRC was also reduced in Asians and those studies with population-based controls and used the PCR-RFLP method. Therefore, detection of the MTHFR C677T polymorphism might be used as markers for CRC prediction and treatment selection.In summary, the present meta-analysis revealed that there was a significant association between


MGMT methylation varied with ethnicity  and control style . In addition, MGMT methylation was observed to be specifically associated with NSCLC clinical stage, and not with age, sex, smoking, pathological types, and differentiation status. Also MGMT methylation did not impact NSCLC patients survival . Our study provided clear evidence about the association of MGMT hypermethylation with increased risk of NSCLC.The relationship between O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) has remained controversial and unclear. Therefore, in this study we have undertaken a systematic review and meta-analysis of relevant studies to quantitatively investigate this association. We identified 30 eligible studies investigating 2714 NSCLC patients. The relationship between MGMT hypermethylation and NSCLC was identified based on 20 studies, including 1539 NSCLC patient tissue and 1052 normal and adjacent tissue samples (OR = 4.60, 95% CI = 3.46~6.11,  It consists of two different histological types, non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC). Among these two, Chinese patients have usually seen higher incidence and mortality rates of NSCLC in the last two decades3. Despite some advances in the therapeutic options for NSCLC in recent times, its prognosis is still very poor with a 5-year overall survival4. Among the many different reasons for poor outcome, epigenetic modification had played an important role in NSCLC carcinogenesis6. For instance, it has been seen that DNA methylation typically is associated with silencing the expression of many tumor suppressor genes in the existing cellular pathways7. Thus, it requires investigation and identification of specific gene methylation patterns that might be helpful for NSCLC diagnosis and can also act as prognostic markers.Lung cancer has been one of the most common causes of cancer-related death in the world6 position of guanine9. Epigenetic silencing of MGMT gene by its promoter methylation at specific CpG islands results in loss of its activity in various cancers, including lung cancer12. However, different studies have shown varying level of MGMT promoter methylation frequency in NSCLC14. But this discrepancy can be attributed to diverse nature of the clinical samples, such as tissues, serum and bronchoalveolar lavage fluid, that were used for this analysis. To be concise, some meta-analysis studies have reported that MGMT methylation is associated with NSCLC incidence17, but these meta-analysis were based on few studies that involved small number of diverse samples and thus could lead to an erroneous result. Typically, they indicated quite different rates of MGMT hypermethylation from different samples, and only the samples from tumor tissue and plasma showed higher methylation than control group16. Moreover, these studies have also not thoroughly investigated the relationship between MGMT methylation and clinical characteristics of NSCLC. They only reported the risk between MGMT methylation and NSCLC17. It is known that different tumor tissue specimens can have some variation, so we in our study have first summarized all published studies which included just the samples from tumor tissues of NSCLC as much as possible, and then performed the systematic review and meta-analysis to quantitatively assess the association of MGMT methylation with incidence and clinical characteristics of NSCLC. With this extensive and careful meta-analysis, we expect to have a better understanding of the role of MGMT methylation in NSCLC.The O-6-methylguanine-DNA methyltransferase (MGMT), a specific DNA damage reversal repairs protein, has been demonstrated to protect tissues against the toxic and carcinogenic effects of alkylating agents by removing adducts from O43 qualified the required criteria, as shown in Fig. Based on the selection criteria, a total of 128 relevant articles were identified. One article was excluded due to duplicative nature, as one another study had similar information. After careful reading of the titles and abstracts, 75 more articles were excluded, as they were either irrelevant or involved just cell or animal studies. The remaining 52 articles were further reviewed in detail, and 22 of them were additionally excluded, as it was observed that tissue specimens were not exclusively were from NSCLC patient’s. In addition, we were unable to extract useful data and some of them were not in English language. Thus, 30 studiesp < 0.00001, Fig. p = 0.04, Fig. p = 0.31, Fig. p = 0.14, Fig. p = 0.39, Fig. p = 0.06, Fig. p = 0.09, Fig. 30 was retrospective studies. Since there was high heterogeneity  among these trials, we used random-effects model for statistical adjustment. Our results demonstrated that MGMT hypermethylation in NSCLC did not associate with overall survival , control style  and detection method . I2 changed to 27% and 64% in ethnicity subgroup, 50% and 30% in control style subgroup, 53% and 0% in detection method subgroup, compared with 47% of total. The results of subgroup analysis of the association between MGMT hypermethylation and smoking indicated that I2 changed to 66% and 80% in ethnicity subgroup, 52% and 0% in control style subgroup, compared with 72% of total. Therefore, the subgroup analysis implied that the factor of control style influence heterogeneity of the association between MGMT hypermethylation and smoking, ethnicity could not explain the heterogeneity.To investigate the influence of other possible factors on the heterogeneity across studies, we conducted subgroup analysis, according to various confounding factors. Specifically, the patients and controls were stratified based on ethnicity, control style and detection method for subgroup analysis, as shown in Table 2 = 47%) in the analysis between MGMT hypermethylation and NSCLC, and deletion of one study by Kim (2) et al.33, significantly reduced the heterogeneity (I2 = 25%).In addition, we also evaluated the sensitivity of our meta-analysis by removing one study at a time and analyzing the remaining studies to assess the stability of the data. The pooled ORs and HR did not significantly alter after the removal of any one study, thereby establishing the stability of our results, as shown in Fig. p > 0.05 from Begg’s test, indicated that no significant publication bias existed. The funnel plots analysis showed symmetry, as shown in Fig. Further, we also evaluated the publication bias of the selected studies by funnel plot and Begg’s test. If the result of funnel plots showed symmetry and 45. During the early stage of carcinogenesis, epigenetic and genetic alterations are common events, and silencing of this MGMT gene by its promoter methylation is one of the major mechanism for carcinogenesis in tumor tissues of various cancers, including NSCLC46. In recent years, some studies have reported about MGMT methylation in NSCLC, however the persuasive evidence about its role in NSCLC and clinical significance is not very convincing. Thus, we undertook this meta-analysis to identify the association between MGMT promoter methylation and different clinicopathological characteristics of NSCLC.MGMT is a DNA repair gene located on a human chromosome band 10q26, and encodes a high-efficiency DNA repair protein to protect cells and tissues from disintegration by ubiquitination-dependent proteolysis, by removing alkyl groups from the O6 position of guanine nucleotide47, which had also reported similar observations. These findings helped us to speculate that it could be a factor for the NSCLC incidence or its risk. Based on the current technology, DNA methylation patterns of any gene can be detected from all kinds of body fluids. Since DNA methylation is an early event in the tumor initiation and is best-characterized as epigenetic alteration, and has been shown to contribute towards carcinogenesis, it could act as an alternative biomarker49. In this reference, one can say based on our findings that MGMT methylation can have a potential role for the NSCLC diagnosis. In addition, many other studies have reported that number of methylated genes were associated with the clinical characteristics34, however our meta-analyses indicated that MGMT promoter methylation was not associated with any clinical characteristics in NSCLC, except staging. It suggested that the increased ability of proliferation and invasion of NSCLC cells may be associated with MGMT hypermethylation. Inactivation of gene of MGMT could contribute tumor progression. In contrast, the study by Huang et al. has reported that MGMT gene methylation was associated with smoking behavior in NSCLC50. This different observation can be attributed to less number of studies that were analyzed in that study, as only 8 studies including 817 patients were selected. However, our data is based on the analysis of 12 studies, which included 1304 patients. In addition, similar to our observation of MGMT gene methylation not associated with worse NSCLC survival, the study by Chen et al. also confirmed similar results51.Our overall pooled data demonstrated that (1) the frequency of MGMT methylation in NSCLC tissue was much higher than normal tissue samples; (2) MGMT methylation was not correlated with clinicopathological characteristics like age, sex, smoking, pathological types, and differentiated status; (3) MGMT methylation played an important role in the staging and was higher in advanced staged (III and IV) NSCLC tissue than in early staged (I and II) tissue samples; and (4) MGMT methylation could not be a prognostic factor for NSCLC prognosis. MGMT gene promoter methylation is a frequent event in NSCLC tissues showed that the MGMT gene promoter hypermethylation is associated with formation and development of NSCLC. Inactivation of the gene of MGMT play an important role in tumor aberrant progression. Our these observation were consistent with the previously published meta-analyses reports2 = 47%) in our met-analysis. But after deletion of one study conducted by Kim (2) et al.27, the heterogeneity significantly declined (I2 = 25%). Now, it was not very clear about the possible reasons of why the results in their study were so different, but we could speculate that may be the method of MGMT methylation detection was a bit different. As we all know that heterogeneity can be due to different characteristics of the patients, including the ethnicity and control style. To minimize the influence of these confounding factors, we performed subgroup analysis and observed that heterogeneity significantly reduced in several subgroups. High heterogeneity was also observed in smoking  and NSCLC overall survival  meta-analysis. We conducted subgroup analysis and sensitivity analysis in the same way, then we observed that heterogeneity significantly reduced in several subgroups. When using the samples from heterogeneous control, the pooled OR of MGMT methylation in smoking patients was much higher than that in no smoking patients. When using the samples from autologous control, the result was opposite. The reason might be high concentration of MGMT methylation in samples of autologous control. This maybe partly explain the heterogeneity of our study. In sensitivity analysis, the pooled ORs and HR did not significantly alter after the removal of any one study. It suggested the robustness of our results.Importantly, we observed a moderate heterogeneity  databases to identify the relevant studies between, January 1, 1997 to August 10, 2016. The following search terms were used: (“lung”) and (“cancer” or “tumor” or “neoplasm” or “carcinoma”) and (“methylation”) and (“MGMT” or “O6-methylguanine-DNA methyltransferase gene”). In addition, we also manually searched the reference lists from the relevant retrieved articles and reviews.The studies were selected for the meta-analysis based on the following specific selection criteria. The eligible studies included; (1) NSCLC patients specimens evaluated for MGMT methylation, (2) Studies reporting the relationship between MGMT methylation level and clinicopathological parameters or prognosis in NSCLC patients, (3) studies either having the direct information about the hazard ratio (HR) and 95% confidence interval (CI) for survival, or with a sufficient data where these can be calculated, and (4) studies with definitive detection method of MGMT methylation. However, the studies were excluded if they; (1) were only letters, reviews, editorials, expert opinions, case reports, meeting records or conference abstracts, (2) were not written in English, (3) lacked the information about clinicopathological parameters or sufficient data for the estimation of HR with 95% CI, (4) had NSCLC tissue specimens other than the serum, plasma, pleural effusion, sputum and Bronchoalveolar lavage, (5) were studies conducted on cells or animal only, and (6) were duplicate publications.The data from these selected studies was independently extracted and reviewed by two authors, Wang and Chen, according to the predefined criteria from eligible studies. The key characteristics of each study recorded were as follows; first author name, year of publication, country, ethnicity, number of cases, source of sample, MGMT methylation detection method and methylation site and frequency. In addition, the extracted information also included clinicopathological parameters of patients, like age, gender, smoking, histological type of cancer, differentiated status, cancer stage  and prognosis. All these data for study characteristics and clinical responses have been summarized in a table format.To assure the high quality of our research, all included studies were systematically and independently assessed according to the Newcastle-Ottawa scale (NOS) criteria. The studies were scored by two authors as follows: (1) subject selection, 0~4 points, (2) comparability of subject, 0~2 points, (3) clinical outcome, 0~3 points. The NOS scores ranged from 0 to 9 with a score of ≥7 indicating good quality. All the disagreements were resolved by discussion and consensus with a third author, Yong Li.p < 0.05 were considered statistically significant). If the value of HR and 95% CI was not directly provided in any study, then we analyzed the K-M curves using Engauge Digitizer version 4.1 software to calculate HR with 95% CI52. The heterogeneity among different studies was estimated by the Cochran’s Q test (p < 0.05 indicated significant heterogeneity) and I2 statistic 54. If the I2 value was ≥50%, then random effects model was used for meta-analysis, otherwise the fixed effects model was used. Subgroup and sensitivity analysis were performed if a statistically significant heterogeneity was observed in the meta-analysis. The publication bias was assessed by funnel plot56 and Begg’s test57, (p < 0.05 indicated significant publication bias).Meta-analyses were performed using Review Manager 5.3  and STATA 12.0  statistical software. The frequency of MGMT methylation was compared in different clinicopathological parameters and odds ratios (OR), HR and 95% CI were calculated. The pooled OR represented the actual association between MGMT methylation and clinicopathological features. HR implied the hazard of mortality for prognosis (