Autism spectrum disorders and schizophrenia have been associated with an overlapping set of copy number variant loci, but the nature and degree of overlap in copy number variants (deletions compared to duplications) between these two disorders remains unclear.We systematically evaluated three lines of evidence: (1) the statistical bases for associations of autism spectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies; (2) data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially among children, and (3) data on the extent to which the CNVs were associated with intellectual disability and developmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs in autism by pooling data from seven case control studies.Four of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clear statistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup 16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors for schizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as risk factors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal for tests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but were not statistically associated with autism, a notable number of children with the CNVs have been diagnosed with autism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability and developmental, speech, or language delays.These findings suggest that although CNV loci notably overlap between autism and schizophrenia, the degree of strongly statistically supported overlap in specific CNVs at these loci remains limited. These analyses also suggest that relatively severe premorbidity to CNV-associated schizophrenia in children may sometimes be diagnosed as autism spectrum disorder. Recent studies of schizophrenia and autism spectrum disorders have generated large suites of data, indicating that each of these disorders is mediated in part by rare copy number variants (CNVs), with substantial overlap in copy number risk loci between the two disorders -8. TheseOverlap in copy number loci or variants between schizophrenia and autism spectrum disorders may have several possible causes. First, CNV loci may overlap between the two disorders, but the actual variants associated with each of them, such as deletions versus duplications of the same region, or different specific regions, may vary within and between the two disorders. Examples of genes involved in CNVs for this category include APBA2, CNTNAP2, NRXN1, PARK2, and SHANK3 -13.Second, the same CNV may have been reported among individuals with schizophrenia or autism spectrum disorders, or statistically supported as a risk factor for both disorders. Such findings implicate overlapping genetic risk factors and shared etiology, which has been postulated to help explain shared phenotypes, mainly deficits and abnormalities in social development and language. This interpretation, however, runs counter to a large body of non-genetic evidence that differentiates autism spectrum disorders from schizophrenia -17, inclIn this article, data from CNV studies of schizophrenia and autism spectrum disorders are used to evaluate alternative hypotheses  for the CNVs were included for analysis if they met three criteria: (1) previous evidence for statistical association of the CNV with schizophrenia, autism, or both disorders; (2) reports of the CNV in both conditions, from case control, family-based, or case series studies ; and (3) sufficient information on phenotypes associated with the CNVs, especially intellectual disability and developmental, speech or language delay, to assess its effects on childhood development, bearing in mind how individuals were ascertained.Genomic coordinates of the CNVs considered here were defined as in the salient publications  and as p = 0.02; dup 16p11.2 in autism, p = 0.025 in the pooled case control analysis; dup 16p13.1 in autism, p = 0.023 in the analysis by Table 2 in Hannes et al. [Four of the CNVs, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, show clear statistical evidence as autism risk factors, whereas the other eight CNVs considered here, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup 16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, are well supported as risk factors for schizophrenia . DetailFor all of the CNV risk factors for schizophrenia, case reports and case series demonstrate that multiple children with the CNV have been diagnosed with autism, ASD, autistic features, intellectual disability, developmental, speech, or language delays, and/or multiple congenital anomalies Table . Such caWith regard to the predictions of the different models in Table The largest number of CNVs  appears to fit Model 2b of schizophrenia risk with possible false-positive diagnoses of ASDs in childhood. Such putative false-positive interpretations are based on a combination of four lines of evidence: (1) strong statistical evidence from studies of schizophrenia for the CNV as a risk factor in this disorder; (2) reports of the CNV in some individuals with ASD from large-scale, case control CNV studies of ASD or autism, but with lack of its documentation as a statistically based risk factor for ASD or autism from case control studies; (3) reports of the CNV in ASD or autism cases from case series and case report-based studies that are designed and presented in non-statistical contexts; and (4) the presence, among children with the CNV, of a high frequency of some combination of intellectual disability, developmental delay, or speech or language delay , conditiDiagnoses of premorbidity to schizophrenia as autism spectrum disorder might be expected in CNV studies for several additional reasons, from previous studies:1. Schizophrenia involves well-documented premorbidity, in a substantial proportion of cases, which centers on developmental, social, and language deficits -78. In c2. Compared to disease-associated SNPs, disease-associated CNVs tend to be rare, more-highly penetrant, syndromic genetic risk factors ,92,93. Tp = 0.0001) and may have been more likely to exhibit diagnoses of a PDD (p = 0.10) compared to such children lacking these CNVs. Additional evidence comes from studies by Ingason et al. [3. Numerous cases have been reported in the literature of individuals diagnosed with autism spectrum disorders in early to middle childhood, and schizophrenia in late childhood, adolescence, or early adulthood ,94-100. n et al.  and Chenn et al. , who eacEvaluation of whether ASD diagnoses represent false positives for individuals with schizophrenia-associated CNVs would require longitudinal studies of the individuals involved. Resolution of this question would also benefit from studies of non-clinical individuals bearing risk CNVs, analyses of autism and schizophrenia endophenotypes among individuals with risk CNVs, and studies that focus on the differential diagnosis of autism spectrum disorders in relation to schizophrenia premorbidity in children ,111-117.An alternative interpretation to the false-positive hypothesis for diagnoses of ASD among children with schizophrenia-associated CNVs is that such ASD diagnoses are true positives that are compatible with possible later diagnoses of the same individual with schizophrenia ,99. UndeOne of the primary implications of these results is that hypotheses of autism and schizophrenia sharing substantial genetic etiology with regard to specific CNVs are not strongly supported by the empirical data, and appear to be based in large part on non-statistical evidence from case reports and case series, combining of duplications with deletions for statistical analyses, very small numbers of cases, or pooling of autism or ASD with other diagnoses , which prevents inference concerning which, if any, of the conditions are associated with the focal CNV ,122,123.The authors declare that they have no competing interests.BC conceived the study and wrote the bulk of the manuscript, and HJC organized and compiled relevant CNV data, and helped in assembling and editing the manuscript. All authors read and approved the final manuscript.Association testing of copy number variants in schizophrenia and autism spectrum disorders.Click here for file


Tumor necrosis factor- alpha (TNF-α) is an inflammatory cytokine which may play important role on the immune response may control the progression of cervical lesions. There is a possible association between TNF-α rs1800629 G/A polymorphism and cervical lesions, but previous studies report conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk.Literature searches of Pubmed, Embase, Web of Science, and Wanfang databases were performed for all publications on the association between TNF-α rs1800629 polymorphism and cervical lesions through December 15, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the strength of the association.Twenty individual case-control studies from 19 publications with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models . Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Caucasians but not in Asians. Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer .The meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians. Cervical cancer is the third most common cancer and the fourth leading cause of cancer death among females, accounting for nearly 10% of the total newly-diagnosed cancer cases and 8% of the total cancer deaths An electronic search of the Pubmed, Embase, Web of Science, and Wanfang databases was performed to identify the eligible studies assessing the association between TNF-α rs1800629 polymorphism and risk of cervical lesions. There were no language restrictions and the last search time was the November 16, 2012. We used the keywords and subject terms:  and (“polymorphism” or “variant” or “genotype” or “mutation” or) and (“tumor necrosis factor” or “TNF” or “308 G/A” or “TNF-α” or “rs1800629”). All eligible studies were retrieved, and their bibliographies were checked for other relevant publications.To be eligible for the inclusion criteria in the meta-analysis, the following criteria were used: 1) case-control studies comparing cervical lesions cases with healthy or non-cancer controls; 2) studies evaluating the association between TNF-α rs1800629 polymorphism and risk of cervical lesions; 3) Sufficient genotype data of TNF-α rs1800629 polymorphism were reported. 4) Studies was excluded if they were the following: 1) Case-only studies; 2) Case reports, letters, or reviews; 3) Incomplete data or no usable data were reported; 4) Studies containing overlapping data; 5) Family-based design or related cases and controls were contained.The data extraction was performed independently by two reviewers, and the conflicting data extracted were settled by discussion. A standardized form was used in the data extraction from the published studies, and the following data were extracted: first author, year of publication, country, ethnicity, study design, diagnostic criteria, source of cases and controls, number of cases and controls, types of cervical lesions, genotyping methods, frequencies of TNF-α rs1800629 genotypes, and the confirmation of Hardy-Weinberg equilibrium (HWE) in controls. The quality of included studies was assessed by the confirmation of HWE in controls, and studies without the confirmation of HWE in controls were defined as low-quality studies, while studies with the confirmation of HWE in controls were defined as high-quality studies.2 test. The strength of the associations between the TNF-α rs1800629 polymorphism and risk of cervical lesions was estimated using odds ratios (ORs) and their 95% confidence interval (95%CIs). The following contrasts for the associations between the TNF-α rs1800629 polymorphism and risk of cervical lesions were evaluated: comparison of the variant allele with ancestral allele (A vs. G); comparison of the variant homozygote with the ancestral homozygote (AA vs. GG); comparison of the variant homozygote combined with the heterozygote vs. ancestral homozygote (AA/GA vs. GG); comparison of the variant homozygote vs. ancestral homozygote combined with the heterozygote (AA vs. GA/GG). The I2 statistic to quantify the proportion of the total variation due to heterogeneity were calculated, and a I2 value of more than 50% was interpreted as significant heterogeneity among studies Before the effect estimation of associations between the TNF-α rs1800629 polymorphism and risk of cervical lesions, we firstly tested whether the genotype frequencies of TNF-α rs1800629 genotypes in the controls were confirmed with HWE using the χet al. assessed the associations of TNF-α rs1800629 polymorphism with risks of both cervical cancer and squamous intraepithelial lesions, the data were extracted as two individual studies A total of 117 potentially individual abstracts were found from the the Pubmed, Embase, Web of Science, and Wanfang databases, but only 24 studies were preliminarily identified and were further assessed for inclusion Meta-analysis of all 20 studies showed that there was a significant association between TNF-α rs1800629 polymorphism and cervical lesions risk under two main genetic comparison models  .Subgroup analysis of studies with high quality showed that there was still a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions under two main genetic comparison models  . HoweverSubgroup analysis of Caucasians showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions under all four genetic models . However, subgroup analysis of Asians showed that there was no association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Asians .Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer . But there was no association between TNF-α rs1800629 polymorphism and risk of squamous intraepithelial lesions .Publication bias was investigated by Begg's funnel plot, and funnel plot asymetry was further assessed by Egger's linear regeression test. As shown in the Cervical cancer is mainly initiated by HPV infection, and TNF-α is an inflammatory cytokine which may play important roles in the progression of cervical lesions Cervical cancer is the third most common cancer and the fourth leading cause of cancer death among female in the world. In recent years, the incidence of cervical cancer has increased gradually TNF-α is secreted mainly by activated macrophages, which is an extraordinarily pleiotropic cytokine with a central role in immune homeostasis, inflammation, and host defense There were some limitations in our meta-analysis. Firstly, there was limited number of eligible studies in the meta-analysis of the association between TNF-α rs1800629 polymorphism and risk of squamous intraepithelial lesions. The limited sample size in the meta-analysis may fail to provide enough statistical power to detect a possible or weak effect of TNF-α rs1800629 polymorphism on squamous intraepithelial lesions. Therefore, more studies with large sample are needed to give a more precise estimation of the association between TNF-α rs1800629 polymorphism and risk of squamous intraepithelial lesions. Secondly, the meta-analysis was based on unadjusted data, as the ORs adjusted for the main confounding variables were not available from those studies. To provide a more reliable estimation of the association, more studies with well-design and large sample size are needed to further identify the association. Finally, gene-gene interactions were not fully addressed in the meta-analysis for the lack of relevant data. There are several polymorphisms associated with risk of cervical cancer, such as p53 Arg72Pro mutation and MTHFR gene polymorphisms In summary, our meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians. However, more studies with large sample and well-design are needed to give a more reliable estimation of the association between TNF-α rs1800629 polymorphism is associated and risk of cervical lesions.Checklist S1PRISMA 2009 checklist.(DOC)Click here for additional data file.


In the past decade, a number of cohort studies studies have been carried out to investigate the relationship between the insertion/deletion polymorphism of the gene encoding angiotensin-converting enzyme and risk of restenosis after percutaneous transluminal coronary angioplasties in patients. However, these studies have yielded contradictory results. Genetic association studies addressing this issue are frequently hampered by insufficient power. We therefore performed a meta-analysis of the published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between ACE I/D polymorphism and post-PTCA restenosis risk.Databases including Pubmed, EMBASE, ISI Web of Science, EBSCO, Cochrane Library databases and CNKI were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The random-effects model was applied, addressing heterogeneity and publication bias.P<10−5). In the subgroup analysis by intervention, significantly increased risks were also found in PTCA-stent and PTCA-balloon for the DD genotype of the polymorphism.A total of 33 cohort studies involving 11,099 subjects were included. In a combined analysis, the OR for post-PTCA restenosis of the ACE DD genotype was 1.61 (95% CI: 1.27–2.04; Our meta-analysis showed that the DD genotype of ACE I/D polymorphism was significantly associated with increased risk of restenosis, particularly for PTCA-stent. Coronary artery disease (CAD), including its most severe complication, myocardial infarction (MI), is the leading cause of morbidity and mortality worldwide. Percutaneous transluminal coronary angioplasties (PTCA) is now a well established treatment for widening the lumen of coronary arteries stenosed by atherosclerotic lesions. The main limitation of PTCA is restenosis in 30–40% of patients, typically occurring between 1–3 months Inappropriate activation of the renin–angiotensin system may play a part in the development of many cardiovascular disorders It has been suggested that the incidence of coronary restenosis after a percutaneous coronary intervention is much higher in patients with the angiotensin converting enzyme DD genotype (which is associated with particularly high plasma angiotensin converting enzyme levels) than in others. However, these studies have yielded apparently conflicting results. These disparate findings may be partly due to insufficient power, false-positive results, and publication biases. The interpretation of these studies has been further complicated by the use of different populations. We therefore performed a meta-analysis of the published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between ACE I/D polymorphisms and post-PTCA restenosis risk.Electronic databases  were searched up to March 2013 for all genetic association studies evaluating the ACE-I/D polymorphism and coronary restenosis after percutaneous transluminal coronary angioplasty (PTCA) in humans in all languages. The search strategy contained both medical subject heading terms and text words as follows: “angiotensin-converting enzyme” or “ACE” or “peptidyl-dipeptidase A,” in combination with “angioplasty” or “stent” or “balloon” or “stenting” or “percutaneous” or “PTCA,” and combined with “genetic” or “polymorphism(s)” or “variations(s)” or “genotype” or “gene(s)”.Eligible studies had to meet all of the following criteria: (1) original papers containing independent data which have been published in peer-reviewed journal, (2) genotype distribution information or odds ratio (OR) with its 95% confidence interval (CI) and P-value, (3) restenosis had to be defined as >50% luminal diameter stenosis at follow-up angiography after an initially successful angioplasty procedure, and (4) prospective cohort studies or case–control studies.The following information was extracted independently and entered into separate databases by two authors from each qualified study: first author’s surname, publication year, ethnicity, genotyping method, definition of restenosis, frequency of insertion or deletion genotypes, sex, mean age, and duration of follow up. The results were compared, and disagreements were discussed among all authors and resolved with consensus.We estimated ORs by comparing cases who developed coronary restenosis after a percutaneous coronary intervention with controls who did not within the same study. The per-allele OR of the D allele was compared between cases and controls. Then, we estimated the risks of the heterozygous and homozygous genotypes on restenosis compared with the wild-type homozygous. Cochran’s Q-statistic test was performed to assess possible heterogeneity in the combined studies The combined search yielded 213 references. Study selection process was shown in −5, P(Q) <10−5; Significant association between the ACE I/D polymorphism and restenosis risk were found. Overall, the combined OR for restenosis in patients with the DD genotype was 1.61  and 1.09 , respectively.Significant heterogeneity was present among the 22 studies (P<0.05). In meta-regression analysis, follow up (P = 0.07), mean age of cases (P = 0.11), sex distribution (P = 0.19), did not significantly explained such heterogeneity. By contrast, ethnicity (P = 0.02) and sample size (P = 0.007) were significantly correlated with the magnitude of the genetic effect.Overall, the per-allele OR of I/D polymorphism of ACE for restenosis risk after PTCA-balloon was 1.25 , with corresponding results for ID heterozygous and DD homozygous of 1.04  and 1.39 .In interpreting the results, some limitations of this meta-analysis should be addressed. Firstly, our results were based on unadjusted estimates, while a more precise analysis should be conducted if all individual raw data were available, which would allow for the adjustment by other co-variants including age, ACE inhibitors using, drinking status, cigarette consumption, and other lifestyle. Secondly, in the subgroup analysis by ethnicity, the number of studies and subjects analyzed was small, and the statistical power was so low that caution should be taken in interpreting these results. Thirdly, although the funnel plot and Egger’s test showed no publication bias and although an exhaustive literature search was done, it is likely that some publications and unpublished data were overlooked. Selection bias for the meta-analysis might have occurred.To conclude, our meta-analysis showed that the DD genotype of ACE I/D polymorphism was significantly associated with increased risk of restenosis, particularly for PTCA-stent. It is also known that the pathogenesis of post-PTCA restenosis is complex and polygenetic in the vast majority of patients, with several genes, each with a small to moderate effect, acting individually, together or in association with important environmental determinants. Larger studies of different ethnic populations, especially with detailed individual information, are needed to confirm our findings.Figure S1Test publication bias on studies of the DD of I/D polymorphism of ACE and restenosis using Egger test.(TIF)Click here for additional data file.Table S1Characteristics of studies included in a meta-analysis of the association between ACE I/D polymorphism and restenosis risk.(DOCX)Click here for additional data file.Checklist S1(DOC)Click here for additional data file.


Methionine is one of the key components of one carbon metabolism. Experimental studies indicate that methionine may reduce inflammation-induced colon cancer. However, epidemiologic findings as to whether dietary methionine intake influences colorectal cancer incidence in humans are inconsistent. To investigate the relationship between dietary methionine intake and risk of colorectal cancer by performing a meta-analysis of prospective studies.Eligible studies were identified by searching PubMed and Embase and by reviewing the bibliographies of the retrieved publications. The summary risk estimates were computed using both a random- effects and a fixed-effects model. Eight eligible prospective cohort studies involving 431,029 participants and 6,331 colorectal cancer cases were identified. According to the random-effects model, the summary relative risks (RRs) for the highest compared with the lowest intake of methionine were 0.89  for colorectal cancer, 0.77 (95% CI = 0.64 - 0.92) for colon cancer, and 0.88 (95% CI = 0.55-1.42) for rectal cancer. In the stratified analysis, a significant inverse association between dietary methionine intake and risk of colorectal cancer was observed in studies with longer follow-up time , in Western studies  and in men . We found no indication of publication bias. This meta-analysis indicates that dietary methionine intake may be associated with decreased risk of colorectal cancer, especially colon cancer. More prospective studies with long follow-up time are needed to confirm these findings.  Colorectal cancer (CRC) is the third most common type of cancer worldwide, accounting for more than one million cases and 600 thousand deaths every year . It is eOne-carbon metabolism is characterized by integrated metabolic pathways centered on folate and methionine metabolism. The term one-carbon refers to one-carbon groups, such as methyl, methylene, methenyl and formyl ,5. One-c Dietary folate intake has long been suggested to be associated with decreased risk of CRC, although the findings are not totally consistent . RegardiTo date, several epidemiologic studies examining the association between dietary methionine intake and risk of incident CRC have been carried out, but the findings are conflicting -18. We cmethionine combined with colorectal or colon or rectal. No language restrictions were imposed. We also searched the reference lists of included publications to identify any further studies. Studies included in this meta-analysis had to meet the following criteria: the study design was prospective; the exposure of interest was dietary intake of methionine; the outcome of interest was incident CRC ; and the relative risks (RRs) or hazard ratios (HRs), with the corresponding 95 % confidence intervals (CIs) were reported. In case the same study was published in more than one article, we included the one containing the largest number of events. We performed a systematic search of PubMed (http://www.ncbi.nlm.nih.gov/pubmed) and Embase (http://www.embase.com) databases up to July 2013 by using the search terms On the basis of these inclusion criteria, one study  was exclTwo author (Z.-Y.Z. and X.-Y.W) independently collected the following characteristics for each study: the first author’s last name, publication year, study location, length of follow-up, number of CRC cases and participants, age, sex, the method used in methionine intake assessment, RR from the most fully adjusted model for the highest compared with the lowest methionine intake and the corresponding 95 % CI, and adjustment for potential confounder in a multivariate analysis. I2 statistics [I2 statistic, a value of ＞50% was considered severe heterogeneity. RRs or HRs were extracted from the selected publications, and their SEs were calculated from the respective CIs. The summary RRs with 95% CIs were calculated using both a fixed-effects model and a random-effects model . Heterogatistics . For theSubgroup analyses according to years of follow-up, number of CRC cases, geographic location, sex, and subsites within colorectum were also performed to assess potential effect modification of these variables on outcomes. In addition, we also conducted a dose–response analysis by using the method proposed by Greenland and Longnecker  to compuPotential publication bias was evaluated with Begg’s funnel plots and Egger’s regression asymmetry test . All anan = 4), Canada (n = 1), Netherlands (n = 1), China (n = 1) and Japan (n = 1). The follow-up period ranged between 5.8 and 22 years. Diet including methionine intake was collected by either self-administered or interview-based food frequency questionnaire (FFQ). Most of included studies reported RRs (95% CIs) of CRC that were controlled for age (n = 7), body mass index (BMI) (n = 7), smoking (n = 7), physical activity (n = 5), family history of CRC (n = 4) and intakes of energy (n = 7), alcohol (n = 8), calcium (n = 7), meat (n = 6) and folate ( n= 4) ( ( n= 4) . P for heterogeneity = 0.18, I2 = 29.1%). RR estimates of CRC for the highest compared with the lowest category of dietary methionine intake for individual studies and all studies combined are shown in P for test = 0.06) lower risk of CRC. The results of the dose-response meta-analysis also suggested an inverse association between dietary methionine intake risk of CRC, though only the results based on the random-effect model was not statistically significant . P for Egger’s test = 0.63).There was no indication of publication bias from either visualization of the funnel plot  or EggerTo the best of our knowledge, this is the first meta-analysis of the prospective association between dietary methionine intake and risk of incident CRC. Results from this large analysis including 6,331 CRC cases and 431,029 participants suggest that dietary methionine intake may be associated with reduced risk of CRC, especially colon cancer. In the subgroup analysis, a significant inverse association was observed when pooling studies with a follow-up period of at least 13.3 years, but no association was found when combining those with a shorter duration. Several possibilities may explain this finding. Clearly, studies with shorter follow-up have had lower number of cases and less power to detect associations. Moreover, both two Asian studies, which appeared to be outliers (reported RRs of ＞1), followed up for less than 10 years, and so the difference by follow-up time may have occurred by chance. However, this finding might also suggest that the latency time between methionine intake and the clinical detection of CRC might serve as an effect modification of the association. Recent evidence from large prospective studies documents that total folate intake in the remote past (12-16 years before diagnosis), rather than close to diagnosis (0-8 years) was associated with reduced risk of CRC; furthermore, the investigators also found that intake close to diagnosis (0-8 years) was most strongly associated with lower risk of colorectal adenoma, indicating that folate intake may be beneficial only during early preadenoma stages . Both meS-adenosylmethionine (SAM), which is the primary methyl donor for methylation process [There are several mechanisms whereby dietary methionine intake may reduce the risk of CRC. Mehionine is an important naturally occurring biomolecule found in all mammalian cells, and is required for the synthesis of  process ,37. In e process . Animal  process . Further process . This meta-analysis has several strengths. Limiting the analysis to prospective studies could eliminate the possibility of recall bias and selection bias that are universal in the retrospective case-control studies, and including more than six thousand CRC cases also minimizes the possibility that the observed findings are chance results. We have also acknowledged that this study has several limitations. First, we cannot resolve uncontrolled confounders as a potential explanation for the observed association, because a meta-analysis of observational studies cannot exclude residual or unknown confounders that could be inherent in the original studies. For example, individuals with higher dietary methionine intake may be at lower risk of CRC due to other health habits. However, this likelihood was largely reduced by the multivariable adjustment of included studies. Most included studies were controlled for age, BMI, smoking, alcohol drinking, physical activity and intakes of energy, calcium and meat. Second, diet intake was assessed by a self-administered FFQ in most included studies, and all but two  of incluIn summary, findings of this meta-analysis suggest that dietary methionine intake may be associated with reduced risk of CRC, especially colon cancer. Future prospective studies with long follow-up durations are needed to confirm these findings. Table S1Characteristics of the included prospective studies.(DOCX)Click here for additional data file.


PPARγ2 and coronary artery disease (CAD). We sought to estimate the inconsistent results by performing a comprehensive meta-analysis.Contradictory results have been reported regarding the association between Pro12Ala polymorphism of Studies in English or Chinese publications were identified by screening MEDLINE, Embase, CNKI, Wanfang and CBM. 22 studies including 8948 cases and 14427 controls were selected. A random-effects model was applied to combine the divergent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias.heterogeneity = 0.67, I2 = 0%) and the homozygote comparison  was observed. In the subgroup analysis by ethnicity, carriers of AlaAla homozygotes had a significant increased risk for CAD among Caucasians . After dividing into population source, the CAD risk magnitude of hospital-based studies was distinctly strengthened under the recessive model  and the homozygote comparison . There was no observable publication bias as reflected by funnel plot and Egger’s linear regression test .The Pro12Ala polymorphism of control population followed Hardy-Weinberg equilibrium for all studies (P>0.05). Overall, a marginal increased risk of CAD under the recessive genetic model (AlaAla vs ProAla+ProPro: P = 0.04, OR = 1.31, 95%CI 1.01–1.69, PPPARγ2 Pro12Ala polymorphism might be risk-conferring locus for the progression of CAD among Caucasians, but not among Asians.Our results demonstrated that the  Coronary artery disease (CAD) and myocardial infarction (MI), the leading causes of morbidity and death in industrialized countries, represent heavy economic and social burdens on the public health system. CAD and MI are common disorders resulted from the interaction of numerous risk factors PPARγ), located on chromosome 3p25, is a member of the nuclear receptor superfamily. PPARγ is considered as a “master regulator” in the course of glucose homeostasis, lipoprotein metabolism and vascular homeostasis PPARγ2 gene is cytosine-guanine exchange in exon B (codon12) which results proline to alanine (Pro12Ala) substitution in the protein et al.TNF α), leptin, resistin, adiponectin, and plasminogen activator in hibitor-1(PAI-1), which play important roles in the process of inflammation and atherosclerosis. There are evidences that the resulting mutant transcription factor profoundly affects the energy metabolism and energy balance and is associated with the risks of atherogenesis PPARγ2 Pro12Ala polymorphism and CAD, but data are inconsistent PPARγ2 gene Pro12Ala polymorphism with CAD, while addressing between-study heterogeneity and publication bias.The gene peroxisome proliferator-activated receptor γ , Wanfang, CBM  electronic databases by using the following combinations of text search string: ‘Pro12Ala’, ‘Peroxisome proliferator -activated receptor gamma’ and ‘coronary’ or ‘CAD’ or ‘myocardial infarction’ or ‘MI’. We also retrieved additional studies through the MEDLINE option ‘related articles’ and manual bibliography review was added. References from the retrieved articles, reviews, and previous meta-analysis were also screened to complete the data bank. If the data were incomplete in an appropriate format, we connected to the corresponding author to obtain the data. The following constraints were applied to the search: (1) Articles published in English or Chinese journals or their supplements; (2) Studies in human subjects without country restrictions; (3) When studies from the same research group with overlapped population were found, only the one with largest population was included to avoid data duplication; (4) Have available genotype frequency; (5) If articles containing more than one geographic or ethnic heterogeneous group, each group was treated separately; (6) genotype distribution of control population must be consistent with Hardy-Weinberg equilibrium (HWE).To identify all studies that examined the relationship between CAD was defined as documented evidence of a previous MI, coronary bypass operation or coronary catheterization findings of significant stenosis of 50% or more in at least one major coronary artery together with clinical symptoms of angina Pro12Ala according to different cohort: First author’s name, publication year, geographic location and population ethnicity, study design, population source, diagnostic criteria, baseline characteristics of the study population , the proportion of diabetes and smoking, the Pro12Ala genotype frequency in patients and controls, genotyping methods and consistency of genotype frequencies with Hardy-Weinberg equilibrium (HWE). Quantitative variables expressed as mean ± standard deviation (SD) or median (5th and 95th percentiles).With the purpose of extracting the necessary characteristics, all relevant articles were collated independently and entered into separate databases by two investigators (ZW and Y. Lou). They checked for any encountered discrepancies and reached a consensus. The following information was collected on the genotype of The quality of studies was also separately assessed by the same two investigators. Quality scoring criteria were modified from the genetic association study by Thakkinstian et al PPARγ2 pro12ala polymorphism and CAD risk by calculating odd ratio (OR) with 95% confidence interval (CI). The result of allele comparison (Ala vs Pro), the dominant genetic model (ProAla+AlaAla vs ProPro), the recessive genetic model (AlaAla vs ProAla+ProPro), and homozygote comparison (AlaAla vs ProPro) were obtained through assessing the pooled studies’ ORs. The random-effects model using the DerSimonian & Laired method was applied to calculate individual effect size together and the Mantel-Haenszel model 2 statistic (ranging from 0 to 100%) was also documented to estimate the degree of heterogenetic variation et al.et al.et al.; Prospective Study of Myocardial Infarction [PRIME] and Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology [ADVANCE] by Dallongeville et al.). Although the predominant ethnicity of these studies was Caucasian, these four studies were performed in different geographical population  and in distinct periods . Considering the heterogeneity of environment exposures of the different region and era, we regarded these studies as four independent studies in our meta-analysis. Then we estimated the other study characteristics that could classify the studies into subgroups with homogeneous effects, such as study design, population source and endpoints.We examined the extent of the association between the Cumulative-analysis was performed to determine the impact of the first published research on the subsequent publication and the evolution of the pooled estimates over time in accordance with the ascending date of published articles.2 statistic and Egger’s test was considered to be statistically significant. HWE was tested by the chi-square test or Fisher's exact test for goodness of fit based on a Web program (http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl). Review Manager software release 5.0  and Stata 11.0  were used for combined data in all studies, and all P values were 2-sided.Sensitivity analysis was conducted by sequential deleting a single study each time in an attempt to identify the potential influence of the individual data set to the pooled ORs. Furthermore, meta-regression was used as an extension to random-effects meta-analysis. In addition, we used the funnel plot to estimate potential publication bias. The standard error of log (OR) of each study was plotted against its OR. An asymmetric plot suggested publication bias probably. Egger’s linear regression test PPARγ2 Pro12Ala polymorphism and CAD was provisionally included. Among these studies, 8 articles were further excluded: 2 study et al.et al.HWE = 8.865×10−7 & 0.044). These two articles were excluded. Two studies had insufficient data, so we tried to connect with the corresponding or original authors for detailed data by E mail. Until recently, the raw data by Ho JS et al.et al.The flowchart summarizing the process of study search and selection was presented in 20 articles included 22 studies with sufficient information were identified in the light of the inclusion criteria PPARγ2 Pro12Ala genotypes and alleles in the individual studies was listed in 22 studies comprising 8948 cases and 14427 controls were selected for the meta-analysis. The baseline characteristics of the qualified studies were summarized in PPARγ2 Pro12Ala polymorphism and CAD risk under different genetic models. Overall, We did not detect any significant association under the allele comparison  and under the dominant genetic model with heterogeneity . However, a marginal increased risk of CAD under the recessive genetic model  and the homozygote comparison  was observed for all the subjects  and the homozygote comparison  compared with the overall estimation  and mixed-blood population .We conducted a series of subgroup analysis on ethnicity, study design, population source and endpoints to explore the potential causes of the heterogeneity . Data oftimation . In contheterogeneity = 0.87, I2 = 0%) and the homozygote comparison  . Further analysis stratifying on study design (prospective versus retrospective) or endpoints (CAD versus ACS versus MI) yielded no significant association under the four genetic models in all the subgroups.A further subgroup analysis was performed in light of study design. 11 studies included 2642 cases and 4113 controls were H–B and the other half involved 6306 cases and 10274 controls were P-B. After dividing into population source, the CAD risk magnitude of H-B studies was distinctly strengthened under the recessive model  , whereaset al.et al.heterogeneity>0.10) and the total effect estimation remained negative. Meanwhile, similar results was also observed in the subsequent subgroup analysis (Pheterogeneity>0.10). Nevertheless, there was not any single study influencing the pooled ORs significantly in any subgroups.Sensitivity analysis was performed to estimate the heterogeneity among all the studies in our meta-analysis. We sequentially removed the single study every time to ascertain the cause of heterogeneity. As a result, 2 independent studies .The meta-regression was a feasible scenario to identify the further source of heterogeneity. The mean or median value of age and BMI and the proportion of male, smoking and T2DM were involved in the meta-regression. Among these variable, the association of Pro12Ala polymorphism with CAD risk was shown with a low smoking rate under the allele comparison  .PPARγ2 Pro12Ala polymorphism to evaluate the publication bias of the literatures. There was no evidence for remarkable publication bias of the Pro12Ala polymorphism  confirmed by the Egger’s test and Begg’s funnel plot  under the recessive genetic model. The nuance is probably due to the restricted sample size.The definite association of PPARγ2 Pro12Ala polymorphism with CAD risk was different between Caucasians and other ethnic groups. The AlaAla genotype carriers showed a significant 45% risk increase among Caucasians, whereas the significance was lack among Asians and other mixed-blood population. Our result indicated the Pro12Ala polymorphism might be increased risk conferring locus for CAD in Caucasian population, but not in Asian and other population. The consensus has not been reached, suggesting the racial genetic diversity of the PPARγ2 Pro12Ala polymorphism plays an important role in the etiology of atherosclerosis across various ethnic populations. It also should be noticed that the Pro12Ala polymorphism was hypervariable between different ancestries Genetic heterogeneity is inevitable in disease identification strategy Apart from the dramatic impact of ethnicity on total evaluation, another estimate should be treated with caution when studies were stratified by population source. Risk increase given by the AlaAla homozygote in the H-B studies seemed to differ from that in P-B studies, being 85% in H-B studies and 19% in P-B studies under the recessive model. Risk increase was significant in H-B studies but not in P-B studies. Besides the relatively small sample size, population classification was still problematic PPARγ2 Pro12Ala polymorphism with CAD risk in population with lower smoking proportion. Considering smoking is a major risk factor of CAD Furthermore, our meta-regression analysis found out a link of the Although our meta-analysis included relatively large sample size consistent of HWE, there are some methodological limitations should be noticed PPARγ2 Pro12Ala polymorphism in CAD are scarce. Our meta-analysis complements the evidences that the Pro12Ala polymorphism, a loss of PPARγ2 function mutation, may exert pleiotropic and deleterious effects in the development of atherosclerosis.A majority of in vivo studies showed PPARγ2 exerts direct and indirect anti-inflammatory effects in the arterial cells of the vascular wall. PPARγ2 activation reduces the production of macrophage and lymphocyte cytokine, inhibits the growth, proliferation In conclusion,our meta-analysis, comprising 23375 participants,implies that homozygosity of the Ala allele might have a potential increased risk of CAD. The effect is at odds, being stronger in Caucasians and barely significant in Asians. Our meta-analysis also emphasizes the necessity of great caution when trying to interpret and reconcile data observed in different ethnic population. More prospective registered studies are helpful to confirm or refuse the present association.Table S1Criteria of quality assessment for genetic association of the PPARγ2 gene Pro12Ala polymorphism with CAD.(DOC)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


Whether the single nucleotide polymorphism (SNP) Lys751Gln of xeroderma pigmentosum group D(XPD) gene increases susceptibility to head and neck cancer (HNC) is controversial and undetermined. Therefore, we conducted this meta-analysis to systematically assess the possible association between them.The OVID, Medline, Embase, Pubmed, Web of Science databases were searched to identify the eligible studies. The odds ratio (OR) with 95% confidence interval (95% CI) were used to assess the strength of association.A total of 11,443 subjects from eighteen studies were subjected to meta-analysis. Overall, XPD Lys751Gln polymorphism had no association with increased HNC risk under all five genetic models (P > 0.05). In the subgroup analysis by ethnicity and source of controls, still no significant association was found under five genetic models (P > 0.05). In the subgroup analysis by cancer type, XPD Lys751Gln polymorphism had statistically significant association with elevated laryngeal cancer (LC) and nasopharyngeal cancer (NPC) risk under heterozygous comparison and dominant model (P<0.05) and borderline significantly increased risk was found under allele contrast for LC and NPC. Carriers of Lys allele and Lys/Lys genotype may be associated with elevated LC and NPC risk.There is overall lack of association between XPD Lys751Gln polymorphism and HNC risk under all five genetic models and still no significant association was found in the subgroup analysis by ethnicity and source of controls. However, XPD Lys751Gln polymorphism was significantly associated with susceptibility to LC and NPC and the Lys allele and Lys/Lys genotype of XPD Lys751Gln polymorphism may be a risk factor for LC and NPC. However, relatively modest sample sizes were included in this meta-analysis and studies with large sample sizes and representative population are warranted to further clarify this finding.http://www.diagnosticpathology.diagnomx.eu/vs/5628716106316015.The virtual slide(s) for this article can be found here:  Head and neck cancers (HNC) which involve malignant neoplasms of the oral cavity, pharynx, and larynx, are the sixth most common cancers threatening human life worldwide . To dateThe XPD Lys751Gln polymorphism  is caused by A to C transition at codon 751 in exon 23 of XPD gene resulting in the Gln substitution for Lys. The XPD Lys751Gln polymorphism may lead to reduction in helicase activity and DNA repair capacity and may be important in the carcinogenesis and development of HNC ,16.To date, a series of case–control studies have been conducted to clarify the association between XPD Lys751Gln polymorphism and HNC risk. However, the results were inconsistent. Therefore, we performed this meta-analysis in order to precisely assess the possible association of XPD Lys751Gln with the susceptibility to develop HNC.The OVID, Medline, Embase,Pubmed, Web of Science databases (up to July 2013) were searched to identify the studies focusing on the association between XPD Lys751Gln polymorphism and susceptibility to HNC. The formats of search terms were used as follows: “xeroderma pigmentosum group D”, “XPD”, “excision repair cross-complementing group 2”, “ERCC2”, “head and neck cancer”, “oral cancer”, “pharyngeal cancer”, “oropharyngeal cancer”, “nasopharyngeal cancer”, “laryngeal cancer”, “SNP or polymorphism or variant” and the combination of them. The literature retrieval was performed by two authors (H. Lin and D. Lin) independently. Relevant reviews and abstracts of meetings were searched for related studies.Eligible studies which satisfied the following inclusion criteria would be included: 1) the study clearly assessed the association between XPD Lys751Gln polymorphism and HNC risk; 2) HNC was diagnosed by histopathological examination; 3) the normal healthy controls had no diagnosis of HNC. On the other hand, the exclusion criteria was used as follows: 1) studies without normal healthy controls; 2) studies without essential data and information; 3) studies in which the genotype distributions in the controls significantly deviated from Hardy–Weinberg equilibrium (HWE).Two authors (H. Lin and D. Lin) performed the extraction of relevant data respectively from all eligible studies. Disagreement was resolved by discussing between two authors (H. Lin and D. Lin). The relevant data as listed below were extracted: name of first author, publication year, country, ethnicity, source of controls, genotyping method, cancer type, total number of cancer patients and controls, and distribution of genotypes in these two groups and P-value of HWE tested in controls. The categorization of ethnicity comprised Caucasian and Asian. Source of controls was categorized as population-based study, hospital-based study, nested case–control study and mixed study. The categorization of cancer type involved laryngeal cancer, oral cancer and nasopharyngeal cancer.2 statistic to check heterogeneity. P-value of heterogeneity less than 0.1 was confirmed as statistically significant. The summary ORs were calculated under fixed effects model in the case that P-value of heterogeneity was more than 0.1. Otherwise,we used random effects model to perform the data calculation. HWE in controls was assessed by the online program (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). Funnel plots,Begg’s test and Egger’s linear regression method were used to evaluate publication bias. P < 0.05 was confirmed as statistically significant to evaluate the data except heterogeneity test. We conducted subgroup analyses by stratification of ethnicity, source of controls and cancer type.In addition, sensitivity analysis was conducted to verify the impact of individual study respectively. All the data statistics and analyses were conducted using Stata version 12.0 .Pooled Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the association between XPD Lys751Gln polymorphism and susceptibility to HNC on the basis of the distinct genotype and allele frequencies of XPD Lys751Gln polymorphism in two groups. The five distinct genetic models comprised allele contrast (Gln v Lys), homozygous comparison (Gln/Gln v Lys/Lys), heterozygous comparison (Lys/Gln v Lys/Lys), dominant model (Lys/Gln + Gln/Gln v Lys/Lys) and recessive model (Gln/Gln v Lys/Gln + Lys/Lys). We used ISelection process was summarized by the flow diagram in Figure The main results of our meta-analysis under five distinct genetic models were listed in Table In the subgroup analysis by ethnicity and source of controls, still no significant association was found Figure , Table 2In the subgroup analysis by cancer type, XPD Lys751Gln polymorphism had statistically significant association with elevated laryngeal cancer (LC) and nasopharyngeal cancer (NPC) risk under heterozygous comparison and dominant model (P < 0.05, Figure There were no significant heterogeneities for the overall analysis under recessive model and the subgroup analysis by cancer type under homozygous comparison and recessive model (Ph>0.10, Table In this meta-analysis, we used both funnel plots, Begg’s test and Egger’s linear regression method to evaluate the publication bias. There were no obvious asymmetry in the funnel plots. Meanwhile, results of Begg’s test and Eggers’s linear regression method indicated that there were no obvious publication bias (P > 0.05, Figure Sensitivity analysis was performed to reflect the impact of the individual study to the summarized ORs by removing one study each time involved in the meta-analysis.We found that the summarized ORs with 95% CIs under all genetic models were not significantly altered after sensitivity analysis (Figure It has been shown that XPD acting as a key DNA repair protein in the NER pathway is involved in the pathogenesis of cancer and XPD Lys751Gln polymorphism may be involved in the mechanism of carcinogenesis b . To dateOur meta-analysis, which comprised 4,510 HNC patients and 6,933 controls, indicated the following descriptions: first, XPD Lys751Gln polymorphism had no association with increased HNC risk under all five genetic models by overall analysis; second, still no significant association was found under five genetic models in the subgroup analysis by ethnicity and source of controls;third, XPD Lys751Gln polymorphism had statistically significant association with elevated LC and NPC risk under heterozygous comparison and dominant model and borderline significantly increased risk was found under allele contrast for LC and NPC. The Lys allele and Lys/Lys genotype of XPD Lys751Gln polymorphism may be a risk factor for LC and NPC.Some limitations of our study should be interpreted. First, the included studies were carried out mainly in Caucasians and Asians and only three studies were population-based, which increased the limitation of statistical power. Hence, studies with larger sample sizes and representative population should be warranted to verify our findings. Second, we only included published papers, as a result, there may be publication bias across studies, although Begg’s test, Egger’s linear regression method did not show any conspicuous publication bias. Finally, our results were grounded on unadjusted estimates, however, XPD Lys751Gln polymorphism is only one phenotype of HNC and HNC is an intricate disorder, and there are many other factors comprising genes, occupation, lifestyle, gender, a history of smoking or drinking, obesity and environmental factors participating in the development of HNC. If the individual data including confounding factors mentioned above were available, a more precise analysis allowing for the adjustment by other covariants should be performed in the future.In conclusion, there is overall lack of association between XPD Lys751Gln polymorphism and HNC risk under all five genetic models and still no significant association was found in the subgroup analysis by ethnicity and source of controls. However, XPD Lys751Gln polymorphism was significantly associated with susceptibility to LC and NPC. Carriers of Lys allele and Lys/Lys genotype may be associated with elevated LC and NPC risk. The Lys allele and Lys/Lys genotype of XPD Lys751Gln polymorphism may be a risk factor for LC and NPC. However, relatively modest sample sizes were included in this meta-analysis and studies with large sample sizes and representative population are warranted to further clarify this finding.XPD: Xeroderma pigmentosum group D; SNP: Single nucleotide polymorphism; HNC: Head and neck cancer; LC: Laryngeal cancer; OC: Oral cancer; NPC: Nasopharyngeal cancer; OR: Odds ratio; CI: Confidence interval; HWE: Hardy– Weinberg equilibrium.The authors declare that they have no competing interests.HL and DL carried out the meta-analysis study, drafted the manuscript and involved in revising the manuscript critically for important intellectual content. CZ and HL participated in the design of the study and revised the manuscript. All authors read and approved the final manuscript.


GSTM1 and GSTT1 are involved in the detoxification of carcinogens such as smoking by-products, and polymorphisms in these two genes with a result of loss of enzyme activity may increase risk of carcinogenesis. Although many epidemiological studies have investigated the association between GSTM1 or GSTT1 null genotype and head and neck squamous cell carcinoma (HNSCC), the results remain conflicting. To elucidate the overall association of GSTM1, GSTT1 and HNSCC, we included all available studies and performed this meta-analysis.GSTM1, 32 articles for GSTT1, and 15 articles for GSTM1 and GSTT1 in combination were identified by a search in PubMed. Associations beween HNSCC and polymorphisms of GSTM1 and GSTT1 alone and in combination were analysed by software RevMan 5.1. Stratification analysis on ethnicity and smoking status, sensitivity analysis, heterogeneity among studies and their publication bias were also tested. Association was found in overall analysis between HNSCC and GSTM1 and GSTT1 null genotype. Stratified by ethnicity, we found increased risks of HNSCC in carriers with GSTM1 null genotype in Asian, GSTT1 null genotype in South American, and dual null genotype in European and Asian. When stratified by smoking, a more significant association of GSTM1 null genotype with HNSCC risk was observed in smokers.A dataset including 42 articles for GSTM1 and GSTT1 polymorphisms and HNSCC risk.This meta-analysis presented additional evidence of the association between  Head and neck neoplasms are the sixth leading cause of death by cancer ι and μ of the GST superfamily have been paid lots of attention, which are encoded by GSTT1 and GSTM1 genes. The GSTM1 and GSTT1 gene have been localized to chromosome 1p13.3 and 22q11.2. Both of the genes are polymorphic and frequent homozygous deletions of the genes presenting null genotype are associated with loss of the corresponding enzyme activity. Therefore, carriers with null genotype will increase the risk of the development of HNSCC due to the decreased ability to detoxify carcinogens theoretically.Enzymes of the glutathione S-transferase (GST) family are present in eukaryotes and in prokaryotes, which are composed of many cytosolic, mitochondrial, and microsomal proteins. They catalyze various reactions and participate in the phase II biotransformation of xenobiotics. GSTs contribute to the detoxification of by-products of smoking and alcohol and other exogenous chemical carcinogens which may induce HNSCC, so they have been considered as potential candidates for HNSCC susceptibility. Classeset al. indicated modest associations of GSTM1 and GSTT1 genotypes with head and neck cancer risk GSTM1 or GSTT1 is a risk factor of HNSCC development GSTM1 or GSTT1 null genotype with the risk of HNSCC by pooling the new published studies using meta-analysis. The present study included all eligible published case-control studies to establish a relatively comprehensive picture of the relationship between these two genes and HNSCC.In 2003, a meta-analysis conducted by Hashibe GSTT1 and GSTM1 polymorphisms with HNSCC, we conducted the search using the following keywords and subject terms: ‘GSTT1’ or ‘GSTM1’, and ‘squamous’. We also searched the references cited in the articles and included published works. Abstracts, case-only articles, editorials, review articles and repeated literatures were excluded. Of the articles with the overlapping data, we only included the publication with the most extensive information. The inclusion criteria in the current meta-analysis were as follows: (a) they are unrelated studies; (b) identification of squamous cell carcinoma was histologically confirmed; and (c) they have original data of genotype frequency and provided sufficient information to calculate the odds ratio (OR) or P-value.Candidate studies were identified through computer-aided literature searches in PubMed for relevant articles in English and Chinese (1995 to May 2012). To identify all articles that studied the association of GSTT1 and GSTM1. We extracted the following information from each study: first author, year of publication, country, ethnicity, numbers of case and control, smoking status and genotyping information. Disagreements between two reviewers were discussed and resolved with consensus. When essential information was not found in articles, we made effort to get the data from the authors (Two reviewers (Zhang Y and Ni Y) independently examined the studies for inclusion in the meta-analysis and collected data on the genotype of  authors .GSTM1 or GSTT1 null genotype or dual null genotype compared HNSCC vs. controls. Odds ratio (OR) and its 95% confidence interval (CI) were assessed for each study. The Cochran's Q-statistic was used to test heterogeneity, and the heterogeneity was considered statistically significant when P<0.1 GSTM1 and GSTT1 on HNSCC risk. The sensitivity analysis was carried out to test the stability of the pooled effect after excluding individual studies. Begg's funnel plot was used to evaluate publication bias. All above statistical analysis was carried out using the software packages Review Manager (RevMan) 5.1.The meta-analysis for GSTM1 or GSTT1, after discarding 11 articles GSTM1 null genotype and HNSCC, and 32 between GSTT1 null genotype and HNSCC. For the association between dual null genotype and HNSCC, 1 discarded article GSTM1, and seven studies GSTT1 were included.We identified 221 articles through the initial computerized search of published work. After reading titles, abstracts, 55 articles were retained. For the analysis of P = 0.51, I2 = 0%) and GSTM1 in non-smokers . The random or fixed effect model was selected for comparisons with or without heterogeneity, respectively.Cochran's Q tests indicated heterogeneity exist in different studies in the analysis except studies of dual genes in South American  , while no significant association was found in European or South American (For  = 0.05) . In sensAmerican .GSTT1 polymorphism, null genotype was associated with an increased risk of HNSCC  (P = 0.04) GSTT1 null genotype increased the HNSCC risk in South American  (For  = 0.01) . Sensiti = 0.04) .GSTM1 and GSTT1 on HNSCC risk showed that OR of individuals with dual null genotype was elevated  compared to GSTM1 or GSTT1 individual null genotype (P = 0.01) and Asian  populations among GSTM1 and GSTT1 dual null individuals  but not in non-smoking group . However, we did not found any significant associations for GSTT1 in either smokers  or non-smokers   , which mGSTM1, gene-gene interaction, and GSTT1 analysis stratified by smoking status. When one study GSTT1 analysis and two studies GSTM1 analysis stratified by smoking status were omitted, funnel plots illustrated symmetric shape.Funnel plots were performed to assess the publication bias, and these shapes did not suggest any obvious evidence of asymmetry in the analyses of GSTM1 and GSTT1 genes belonging to GSTs have been studied extensively due to their important detoxification function and high-frequency polymorphisms. GSTM1 and GSTT1 homozygous deletions (null genotype) may lead to deficient enzyme activity GSTM1 and GSTT1 null genotype in controls were 47.65% and 23.77% respectively in accordance with other studies GSTM1 and GSTT1 null genotype in controls in European, Asian and South American were 53.14%, 40.06%, 49.29% and 21.86%, 23.67%, 26.34% respectively, which indicated ethnic differences.Genetic factors play an important role in the etiology of tumors. For HNSCC, genes encoding xenobiotic-metabolizing enzymes (XMEs) are some of the most likely candidates that could affect individual's susceptibility to the disease, due to their involvement of the metabolic activation and detoxification of the environmental carcinogens GSTM1 and GSTT1 polymorphisms effects on HNSCC has been a concern in recent years, but the data of existing studies are contradictory. An increase in the risk of HNSCCC was observed in cases with null genotypes of GSTM1 or GSTT1 in some studies GSTM1 or GSTT1 and HNSCC. Although the confused effect of these polymorphisms may be a result of various reasons such as demographic features of subjects and different life styles, comparatively small sample size in individual study might lead to lower statistical power and bias. The present meta-analyses of 42 studies including 7584 cases and 8651 controls for analysis of GSTM1, 32 studies including 6255 cases and 7138 controls for analysis of GSTT1, and 15 studies including 2657 cases and 3092 controls provide more comprehensive information on the relationships between two genes and HNSCC.The importance of GSTM1 and GSTT1 null genotype confers susceptibility to HNSCC in the overall analysis. GSTM1 can deals with large hydrophobic electrophiles including polycyclic aromatic hydrocarbons derived epoxides (PAH) GSTT1 targets a more restricted kind of compounds, like monohalomethane and ethylene oxide GSTM1 and GSTT1 null genotype may theoretically confer a higher risk to HNSCC. Comparing to homozygous deletion of GSTM1 and GSTT1 alone, deletion of two genes in combination significantly increases the risk of HNSCC as showed in our combined analysis, indicating a synergenic role of GSTT1 and GSTM1 in cancergenesis.This meta-analysis showed that both GSTM1 may be an important factor in Asians in the development of HNSCC, which is similar to the results reported by Hashibe et al. GSTT1 but not GSTM1 may be important in South Americans, while GSTM1 and GSTT1 in combination play a vital role in Europeans and Asians. This result may be attributed to the different habits of smoking, alcohol consumption, intake of food and different genetic backgrounds in different ethnic groups.Analyses after stratification by ethnicity revealed ethnicity-specific associations between two genes and HNSCC. Our findings indicate that GSTT1 and GSTM1 can prevent the accumulation of tobacco smoke carcinogens, and compared with non-smokers, mutations of these two genes theoretically increase the risk of HNSCC in smokers. To investigate potential gene-environment interaction, we stratified the data by smoking status. A significant association was observed in smokers with GSTM1, whereas no difference was observed between smokers and non-smokers for GSTT1. Previous studies showed that GSTT1 and GSTM1 are involved in the detoxification of carcinogens such as smoking by-products, and polymorphisms in these two genes with a result of loss of enzyme activity may increase risk of carcinogenesis and have different role in detoxification. GSTM1 null genotype in smokers (OR = 1.51) than non-smokers (OR = 1.14), further individual large study are required to evaluate the interaction of GSTM1 and smoking on HNSCC risk.Both GSTM1, GSTT1 and HNSCC. If available detailed individual data are enough for an adjusted estimate in the future, a more precise analysis should be conducted. Third, ethnicity was determined roughly by subject's country due to inadequate available data, and this classification can help us have a regional concept of these genes functions. Fourth, the controls in the included studies were recruited in different ways and not uniformly defined, which may have distorted the meta-analysis. Finally, because all the studies were designed with retrospective studies, we cannot clearly determine the causal relationship between the risk factor and HNSCC. Given the limitations and biases above, the conclusions or interpretations made from the results of this meta-analysis should be explained with caution.Although our result of this meta-analysis is constructive, its limitations and some potential bias should be addressed. First, despite that a well-designed search strategy was used to identify eligible studies, it was possible that some relevant studies were not included. This study only focused on full-text papers published in English and Chinese in PubMed, so some eligible studies in other languages or in other databases might be missed. Second, adjustments over age, gender and other environmental factors such as alcohol drinking might help better detect the association between GSTM1 and GSTT1 null genotypes may be associated with an increased risk of HNSCC. Further large well-designed studies are warranted to confirm these findings.The results of this meta-analysis suggest that Prisma Checklist S1(DOC)Click here for additional data file.


The association between polymorphisms on 5p12 and breast cancer (BC) has been widely evaluated since it was first identified through genome-wide association approach; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta-analysis on two wildly studied polymorphisms (rs10941679 and rs4415084) on 5p12.Databases including Pubmed, EMBASE, Web of Science, EBSCO, and Cochrane Library databases were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The random-effects model was applied, addressing heterogeneity and publication bias.P = 4.5×10−8) and 1.09  was found for the rs10941679 and rs4415084 polymorphism respectively. Significant results were found in Asians and Caucasians when stratified by ethnicity; whereas no significant associations were found among Africans/African-Americans. Similar results were also observed using dominant or recessive genetic models. In addition, we find both rs4415084 and rs10941679 conferred significantly greater risks of ER-positive breast cancer than of ER-negative tumors.A total of 19 articles involving 100,083 cases and 163,894 controls were included. An overall random-effects per-allele OR of 1.09 (95% CI: 1.06–1.12; Our findings demonstrated that rs10941679-G allele and rs4415084-T allele might be risk-conferring factors for the development of breast cancer, especially in Caucasians and East-Asians. Breast cancer (BC) is one of the most commonly occurring epithelial malignancies in women, with an estimated 1 million new cases and over 400,000 deaths annually worldwide Recently, a genome-wide association (GWA) study conducted in European ancestry (EA) population by Stacey et al. identified two genetic susceptibility loci, rs10941679 and rs4415084, at chromosome 5p12 were associated with BC risk Papers published before the end of May 2013 were identified through a search of Pubmed, SCOPUS, ISI web of knowledge, Embase and Cochrane databases using the following terms: “breast cancer”, or “breast carcinoma”, and “chromosome 5p12”, or “rs10941679” or “rs4415084” and “polymorphism”, or “variation”. The titles and abstracts of potential articles were screened to determine their relevance, and any clearly irrelevant studies were excluded. The full texts of the remaining articles were read to determine whether they contained information on the topic of interest. All reference lists from the main reports and relevant reviews were hand searched for additional eligible studies not indexed by Medline.P-value, (3) genotype distribution of control group must be consistent with Hardy–Weinberg equilibrium (HWE).Eligible studies had to meet all of the following criteria: (1) original papers containing independent data which have been published in peer-reviewed journal, (2) genotype distribution information or odds ratio (OR) with its 95% confidence interval (CI) and The following information was extracted independently and entered into separate databases by two authors from each qualified study: first author's surname, publication date, population ethnicity, source of control subjects, genotyping method, age, and the genotype counts in cases and controls. The results were compared, and disagreements were discussed among all authors and resolved with consensus. For studies including subjects of different ethnic groups, data were extracted separately. Meanwhile, different case–control groups in one study were considered as independent studies. For each study, we did not define a minimum number of patients for inclusion in our meta-analysis.For association studies with inconsistent results on the same polymorphisms, the methodological quality should be assessed by appropriate criteria to limit the risk of introducing bias into meta-analyses or systematic reviews. A procedure known as ‘extended-quality score’ has been developed to assess the quality of association studies. The procedure scores each paper categorizing it as having ‘high’, ‘median’ or ‘poor’ quality. Detailed procedure of the quality assessment was previously described 2I-test were performed to assess possible heterogeneity in the combined studies The meta-analysis examined the association between each polymorphism and the risk of BC, for the: (i) allele contrast, (ii) recessive, and (iii) dominant models Based on our search strategy, the primary screening produced 103 potentially relevant articles. A total of 19 studies published between 2008 and 2012 were included according to our inclusion criteria, involving 100,083 cases and 163,894 controls −8; −7] and recessive  genetic models.In the overall analysis, the rs10941679 polymorphism was significantly associated with elevated BC risk with a per-allele OR of 1.09  in Caucasians. Among Africans/African-Americans, no significant association was found in all genetic models   = 8.6×10−11], while no significant results were found ER-negative tumors   = 0.01] in Asians and 1.12  .−7; −7] and recessive  genetic models  = 4.2×10c models .−5] in small studies compared to 1.07  in large studies. The data on genotypes of the polymorphism among cases stratified by ER status were available in 6 studies including 20,000 cancer cases and 102,686 controls. The interaction between ER status and polymorphism, for which an OR of 1.14  for ER-positive BC appeared in compared with individuals with the ER-negative BC   and 1.10 (95% CI: 1.06–1.14), respectively. No significant associations were detected among Africans/African-Americans . In considering sample size subgroups, the OR was 1.10  .In order to assess the stability of the results of the meta-analysis, we performed a sensitivity analysis through sequentially excluded individual studies. Statistically similar results were obtained after sequentially excluding each study, suggesting stability of the meta-analyses. Begg's funnel plot and Egger's test were performed to identify small studies effects. As shown in Via a comprehensive meta-analysis, we evaluated the association of two common polymorphisms on 5q12 with the risk of BC. Overall results demonstrated that rs10941679-G allele and rs4415084-T allele might be risk-conferring factors for the development of BC in Caucasians and Asians, but not in Africans/African-Americans. Although potential sources of heterogeneity could not be easily eliminated, the present study, to our knowledge, is the first meta-analysis which involved a total of 100,083 cases and 163,894 from 19 studies to date dealing with the association of these two polymorphisms with BC susceptibility.In meta-analysis, heterogeneity evaluation was always conducted in statistical analysis. Thus, several subgroup meta-analyses were performed according to ethnicity, sample size. In the stratified analysis by ethnicity, significant associations were found in Asians and Caucasians for the two polymorphisms in all genetic models; while no associations were detected among Africans. Such result could be due to the limited number of studies among Africans/African-Americans, which had insufficient statistical power to detect a slight effect or different linkage disequilibrium (LD) pattern of the two polymorphisms among Africans. Besides, the frequencies of the risk-association alleles in 5p12 are similar in European and Asian populations, but substantially lower in African descent ER status is known to affect prognosis of BC. Stratification of tumors by ER status indicated that the two SNPs (rs4415084 and rs10941679) on 5p12 confer risk, preferentially for ER-positive tumors, with no risk for ER-negative BC. Results from subgroup analyses on ER status of tumors were in agreement with previous reports 2 = 0.83 in HapMap CHB, r2 = 0.72 in HapMap CEU) and located at a site of H3K4Me3 histone modification marks. Therefore, it is possible that rs4415084 might be a proxy for other potentially functional SNPs, such as rs3761648, that influence MRPS30 expression and in consequence the cancer risk. Although the exact function of this gene is unknown, the apoptotic pathway is likely to be involved in mitigating DNA damage. Given the multifaceted and closely-linked nature of the DNA repair, cell-cycle and apoptotic pathways, it is likely that there are complex polygenic factors underlying the observed interactions of MRPS30 with BC The biological mechanism through which genetic variations in 5p12 influences BC risk remains unclear. rs10941679 and rs4415084 are in a region of high LD as reported by Stacey et al The strengths of this study include the very large sample size, no deviation from HWE, and the high quality of the qualified studies. However, our current study should be interpreted with several technical limitations in mind. First, heterogeneity is a potential problem when interpreting all the results of meta-analysis. Although we minimized the likelihood by performing a careful search for published studies, using the explicit criteria for study inclusion, the significant between-study heterogeneity still existed in most of comparison. The presence of heterogeneity can result from differences in the age distribution, menopause status, environment factors, prevalence lifestyle factors and so on. Second, the vast majority of white subjects in the study are of European descent, and statistical power for analyses in other ethnicities is limited. Because the sample size was considerably smaller for Africans/African-Americans studies, the main conclusions from this manuscript are based on analyses among white European and Asian women. Future studies including larger numbers of Africans/African-Americans are necessary to clarify the consistency of findings across ethnic groups. Third, the subgroup meta-analyses considering interactions between common variations at 5p12 genotype and ER status with BC risk, were performed on the basis of a fraction of all the possible data to be pooled, so selection bias may have occurred and our results may be over inflated. In this context, more reliable results can be expected if individual data are available for a pooled analysis. Finally, lack of individual-level data prevent us from making an adjustment estimates to identify any interactions between genetic variation and clinical traits.Taken together, we have expanded previously individual studies by providing the convincing evidence that MRPS30 gene rs10941679 and rs4415084 polymorphisms at 5p12 might be risk-conferring factors for the development of BC in Asians and Caucasians, but not in Africans/African-Americans. Further studies should investigate the markers on and adjacent to 5p12 to clarify whether the present association is causal or due to linkage disequilibrium.Figure S1Study selection process.(TIF)Click here for additional data file.Figure S2Per-allele ORs and 95% CIs for the association between 5p12-rs10941679 and breast cancer risk by ER status.(TIF)Click here for additional data file.Figure S3Per-allele ORs and 95% CIs for the association between 5p12-rs4415084 and breast cancer risk by ER status.(TIF)Click here for additional data file.Figure S4Begg's funnel plot of 5p12-rs10941679 polymorphism and BC risk.(TIF)Click here for additional data file.Figure S5Begg's funnel plot of 5p12-rs4415084 polymorphism and BC risk.(TIF)Click here for additional data file.Checklist S1(DOC)Click here for additional data file.


C/A polymorphism in fat mass and obesity-associated gene (FTO) was associated with the risk of type 2 diabetes (T2D) in Europeans. But this association was abolished after adjustment for body mass index (BMI), suggesting that the effect of rs8050136 on T2D risk might be mediated by BMI in Europeans. However, the findings in subsequent studies were inconsistent among Asian populations. To determine whether rs8050136 polymorphism in FTO is independently associated with the risk of T2D in Chinese, we conducted a case–control study with 2,925 T2D patients and 3,281 controls in Han Chinese.Genome-wide association study (GWAS) has identified that rs8050136 A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI (odds ratio (OR) = 1.17, 95% confidence interval (95% CI) = 1.03-1.32, p = 0.016). Meta-analysis containing 10 reported studies and our data with a total of 15,819 cases and 18,314 controls further confirmed the association between rs8050136 polymorphism and T2D risk in East Asians .Logistic regression revealed that the FTO may contribute to T2D risk in Han Chinese and rs8050136 polymorphism may be a genetic marker for T2D susceptibility.Our findings indicate that the genetic variant in  Type 2 diabetes (T2D) is a major global health problem with an increasing prevalence over the world. More thFTO) was associated with the risk of T2D in European populations[FTO as strongly associated with both BMI and obesity in Europeans[2 = 1). Therefore, it is suggested that the effect of rs8050136 or rs9939609 on T2D risk may be mediated through a primary effect on obesity in European populations.In 2007, genome-wide association studies (GWAS) firstly reported that single nucleotide polymorphism (SNP) rs8050136 in fat mass and obesity-associated gene  and the additive model . With the adjustment for age, sex and BMI in the logistic regression model, rs8050136 CA/AA genotypes were associated with a significantly increased risk of T2D , as compared with CC genotype. Similar association was also observed in the additive model .The distributions of demographic and selected clinical characteristics of 2,925 T2D cases and 3,281 controls were summarized in . No heterogeneity was observed among these subgroups.We then conducted the stratified analyses by age, sex and BMI. As shown in Table A allele was associated with an increased T2D risk in East Asians . Funnel plot and Egger’s test were used to address the potential publication bias and no significant publication bias was found  between rs8050136 and T2D risk in 864 cases and 864 controls in Japanese[Although a number of studies have investigated the association between Japanese. HoweverJapanese. In the A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI. A recent meta-analysis including 96,551 East and South Asians reported that the minor allele for the rs9939609 FTO SNP (perfect LD with rs8050136) significantly increased the risk of both obesity and T2D, and the association between the FTO locus and risk of T2D remained significant after adjustment for BMI[Our study showed the  for BMI. Interes for BMI. These rFTO gene on chromosome 16. The exact function of the gene product of FTO is not yet understood and how the polymorphism affects the risk of T2D is unclear. Based on sequence homology, FTO gene is predicted to encode a 2-oxoglutarate-dependent demethylase enzyme, which affects nucleic acid demethylation[FTO mRNA and protein in skeletal muscle of T2D patients, suggesting that FTO may involve in T2D pathogenesis through oxidative metabolism, lipogenesis and oxidative stress in muscle defects[The SNP rs8050136 is mapped to the intron 1 of hylation. This ge defects.FTO polymorphism with T2D risk, we cannot rule out the possibility of residual confounding of obesity, because the alternative measures (such as DEXA fat mass) of adiposity were not available in this study. More alternative measures of adiposity need to be considered in future studies.The limitation of this case–control study was that most of the T2D cases were diagnosed before the surveys and therefore, their BMI may not be a perfect measure of adiposity, particularly in lean individuals and in East Asians who usually have more abdominal fat and less muscle mass than Caucasians. Although we adjusted BMI for adiposity in detecting the association of FTO rs8050136 polymorphism with the risk of T2D in a large case–control study and 2 meta-analyses and confirmed that the A allele was significantly associated with an increased risk of T2D in East Asians. Further studies are warranted to clarify the potentially biological mechanisms of FTO rs8050136 polymorphism in T2D pathogenesis.In summary, we evaluated the association of 2 ≤ BMI < 28 kg/m2, and obesity as BMI ≥ 28 kg/m2[All subjects were genetically unrelated ethnic Han Chinese and the study population was previously described,23. In b 28 kg/m2. The disGenomic DNA was isolated from leukocyte pellets of venous blood by proteinase K digestion, followed by phenol-chloroform extraction. TaqMan OpenArray Genotyping System  and the iPLEX Sequenom MassARRAY platform  were used to perform genotyping. Genotype was successfully detected in 2,898 cases and 3,262 controls, with the call rate being 99.2%. Genotyping was performed by technicians without knowing the statuses of T2D cases or controls. Two blank controls in each plate were used for quality control. 96 randomly selected duplicated samples were examined on two platforms and the concordant rate was 100%.FTO gene rs8050136 polymorphism and T2D risk in East Asian populations. Eligible studies, published in English, up to August, 2012, were identified by using the search terms “FTO and polymorphism and type 2 diabetes” in PubMed. Studies that were not conducted in East Asians were excluded in manual. ORs and 95% CIs were calculated in additive model after adjustment in logistic regression. Cochran’s χ2-based Q-statistic test was performed to assess the heterogeneity among the included studies. The combined OR was calculated using the Mantel–Haenszel method in fixed-effect model with 95% CI in Woolf’s method as there was no significant heterogeneity. Publication bias was evaluated with Egger’s t test.We searched all case–control studies on the association between t-test for continuous variables and the χ2 - test for categorical variables. The Hardy-Weinberg equilibrium was tested by a goodness-of-fit χ2 - test in controls. The association between SNP and T2D risk was estimated by computing the ORs and 95% CIs using unconditional logistic regression analysis after adjustment for age, sex and BMI. Heterogeneity test for stratified analyses of the selected variables was conducted with the χ2-based Q test. Multivariate linear regression analyses were performed to test the correlation between the genotypes and quantitative BMI trait after adjustment for age and sex. The statistical power was calculated by PS  3.0.2 software. All statistical analyses were performed by using STATA version 11.0 .The differences in demographic variables, selected variables, and frequencies of the genotypes between cases and controls were evaluated by using the Student’s GWAS: Genome-wide association study; FTO: Fat mass and obesity-associated gene; T2D: Type 2 diabetes; BMI: Body mass index; OR: Odds ratio; 95% CI: 95% confidence interval; SNP: Single nucleotide polymorphism; LD: Linkage disequilibrium; FBG: Fasting blood glucose; TC: Total cholesterol; TG: Triglyceride; HDL-C: High-density lipoprotein-cholesterol; HWE: Hardy–weinberg equilibrium; MAF: Minor allele frequency.The authors declare that they have no competing interests.YQ carried out the molecular genetic studies, participated in the genotype detection and statistical analysis, drafted the manuscript and is the corresponding author. SL and FL performed the experiments and analyzed the data. HL participated in the genotype detection and the statistical analysis. MD and YL participated in the field investigation. JD, JG and YL participated in the genotype detection. GJ and JD participated in the design and the data analysis. ZH involved in the design and coordination. HS conceived the study, edited the manuscript, and is the corresponding author. All authors read and approved the final manuscript.General characteristics of type 2 diabetes cases and controls. This table shows the characteristics of the study population. No significant differences were observed in the distributions of sex, smoking and drinking status. Type 2 diabetes cases were older than controls and had significantly higher levels of body mass index, fasting blood glucose, triglyceride, total cholesterol, blood pressure and significantly lower level of high-density lipoprotein cholesterol.Click here for filePublished studies on the association between rs8050136 polymorphism and the risk of type 2 diabetes in East Asians. The table displays minor allele frequencies (MAFs), sample sizes, adjusted odds ratios (ORs) and 95% confidence intervals (CIs), p-values, populations, journals, authors and published year of the 10 published studies among East Asian populations. They were included in the meta-analyses together with the present study.Click here for fileMeta-analysis of the association of rs8050136 polymorphism with the risk of type 2 diabetes in Han Chinese. The figure shows the results of the meta-analysis covering 6 reported studies in Chinese Han populations and our present study.Click here for fileFunnel plot analysis to detect the publication bias in Chinese Han populations. The figure shows the results of the funnel plot analysis to address the potential publication bias about the 7 studies conducted among Chinese Han populations.Click here for file