IL-10 gene polymorphisms with systemic lupus erythematosus (SLE) susceptibility. However, their results are conflicting.A number of observational studies have been conducted to investigate the association of the IL-10 polymorphisms and SLE in PubMed, EMBASE and Chinese Biomedical Literature Database. A meta-analysis was conducted using a fixed-effect or random-effect model based on between-study heterogeneity.We searched published case-control studies on the IL10.G microsatellites , the G allele of the IL-10 -1082G/A polymorphism  and its associated haplotype -1082G/−819C/−592C  were associated with increased SLE susceptibility without or with unimportant between-study heterogeneity. Removing studies deviating from Hardy-Weinberg equilibrium (HWE) hardly changed these results. Among Asians, the CA21 allele of the IL-10.G microsatellites  and the -1082G/−819C/−592C haplotype  were associated with increased SLE susceptibility, but with substantial between-study heterogeneity or sensitive to HWE status. Removing studies deviating from HWE also produced statistically significant associations of the IL-10 -1082G/A  and -592C/A polymorphisms  with SLE among Asians.A total of 42 studies with 7948 cases and 11866 controls were included in this meta-analysis. Among Caucasians, the CA27 allele of the IL10.G microsatellites, the IL-10 -1082G/A and -592C/A polymorphisms and the haplotype -1082G/−819C/−592C are associated with SLE susceptibility. Besides, this is the first time to report an association between the CA27 allele of the IL-10.G microsatellites and SLE among Caucasians. Further studies are needed to confirm these findings.This meta-analysis showed that the  Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disorder with diverse clinical manifestations. It can be potentially fatal when major organs are affected. The prevalence of SLE ranges from approximately 20 to 150 cases per 100,000 persons worldwide IL-10 gene is a candidate gene for SLE susceptibility. IL-10 enhances B cell proliferation, differentiation and antibody production, and therefore plays a role in B cell hyperactivity and in increasing production of autoantibodies in SLE Interleukin 10 (IL-10), primarily produced by monocytes and lymphocytes, is a multifunctional cytokine in immunoregulation and inflammation. There are several lines of evidence suggesting that the IL-10 gene is located on chromosome 1q and encodes for 5 exons. The IL-10 promoter is highly polymorphic and in this region two CA-repeat microsatellites (IL-10.G and IL-10.R) and three single nucleotide polymorphisms (SNPs) at positions −1082, −819, and −592 from the transcription start site, have been identified to correlate with IL-10 production In humans, the IL-10 gene polymorphisms and IL-10 production, a number of observational studies have been conducted to investigate the association of the IL-10 gene polymorphisms with SLE susceptibility. However, their results are conflicting. This can be due to insufficient power, small effect of the IL-10 gene polymorphisms on SLE susceptibility, and false-positive results. Meta-analysis is a statistical method that can overcome the limitations of individual studies IL-10 gene polymorphisms and SLE susceptibility.Considering the role of IL-10 in SLE and the relationship between the IL10 gene polymorphisms and SLE risk, no matter which polymorphisms were studied or whether they provided enough data to calculate odds ratios (ORs). Family-based studies were excluded because of linkage considerations.We searched PubMed, EMBASE and Chinese Biomedical Literature Database for relevant reports without language restriction. The last search update was performed on August 31, 2012. The search strategies were based on the following form: (interleukin-10 or synonyms) AND (“systemic lupus erythematosus” or synonyms). Both thesaurus terms and free text were used. Detailed description of the search strategies can be found in supplementary materials see . We alsoIL10 genotypes, and consistency of genotype frequencies with Hardy-Weinberg equilibrium (HWE). We compared author names, authors’ affiliations, and geographic locations and period of studies to identify sequential or multiple publications. If more than one report related to the same or overlapping data sets, we included results from the largest or most recent publication.Two authors  independently screened all reports by title or abstract for those requiring further retrieval, and then independently reviewed these studies for eligibility. Discrepancies were resolved by group discussion. Following information was extracted using predetermined forms: the first author’s name, year of publication, ethnicity, definition and numbers of cases and controls, genotyping method, frequency of IL10 gene polymorphisms and SLE risk. For each allele or haplotype with enough data sets, we performed overall analysis as well as subgroup analysis on the basis of population ethnicity and HWE in control groups, as genotype frequencies are often different across ethnicities and deviating from HWE may be a sign of selection bias or population stratification. HWE was tested using the χ2 test and it was considered statistically significant when the P value is less than 0.05 We calculated odds ratios with 95% confidence intervals (CIs) to assess the strength of the association between the For SNPs, we adopt four genetic models to evaluate their association with SLE risk: major allele vs. minor allele, major allele homozygotes vs. minor allele homozygotes, major allele homozygotes vs. heterozygotes plus minor allele homozygotes, and major allele homozygotes plus heterozygotes vs. minor allele homozygotes.P value from the χ2 test (Cochran’s Q statistic) and the I2 statistic. The I2 statistic represents the proportion of variation in the study estimates due to heterogeneity, in which 0–40% may be unimportant heterogeneity, 30–60% indicates moderate, 50–90% indicates substantial and 75–100% indicates considerable heterogeneity P value from the χ2 test was more than 0.10, the summary OR estimate was calculated by the fixed-effect model Heterogeneity was determined using the By screening title or abstract and further evaluating full-text, we identified 38 case-control studies from PubMed and EMBASE and 8 from Chinese Biomedical Literature Database. 5 of them were excluded because of duplication reports or using the same or overlapping data sets. One publication contained two individual case-control studies. At last, 41 publications with 42 case-control studies were included in this review see . Figure These 42 case-control studies were published from 1997 to 2011 with 33 in English, 6 in Chinese, 1 in Russian and 1 in Bulgarian. They included 7948 cases and 11866 controls. All studies used healthy people as controls. Ethnic groups among these studies were as following: 20 were Asians, 16 were Caucasians, 2 were Mexicans, 1 was African, 1 was Colombian, 1 was Kazakh, and 1 was mixed populations. IL-10 gene polymorphisms with SLE, 11 studied the IL10.G microsatellites, 6 studied the IL-10.R microsatellites, 24 studied −1082, 20 studied −819, 26 studied −592, 4 studied −3575 and 4 studied −2763. For other SNPs, there was only one study.Of the 42 studies investigating the association of the IL10.G microsatellites and SLE susceptibility, 10 provided enough data to calculate ORs  and there was no significant between-study heterogeneity. Further subgroup analyses showed that this association was found among Caucasians , but not among other populations. Subgroup analyses also showed that the CA21 allele of the IL10.G was associated with SLE among Asians . But there was substantial between-study heterogeneity. As described previously, we also divided all alleles of the IL10.G microsatellites into long allele (>21 CA repeats) and short allele (≤21 CA repeats). No association was found between them and SLE.Of the 11 studies investigating the association between the late ORs . By poolIL10.R microsatellites, only 3 studies were available to calculate ORs. They all studied Caucasians. The meta-analyses found no association between the IL10.R microsatellites and SLE.For the IL10 −1082G/A polymorphism and SLE susceptibility, 23 provided enough data to calculate ORs .Of the 24 studies investigating the association between the late ORs . The resIL10 −1082G allele was associated with increased SLE risk among Caucasians under three genetic models , while the associations were not found among Asians under any genetic model. After excluding studies deviating from HWE In the subgroup analyses by ethnicity, the results showed that the PEgger’s test>0.05, The heterogeneity was significant in the pooling analyses of total available studies and in the subgroup analyses of Asians. Deviating from HWE in control groups can explain much of it. When excluding studies deviating from HWE could not eliminate the heterogeneity or eliminate it little, we excluded one more study. By this way, we found that the study by Shen contributed much heterogeneity in the pooling analysis and the subgroup analysis of Asians IL10 −819C/T polymorphism and SLE susceptibility, 18 provided enough data to calculate ORs . A close but not statistically significant association was found under the genetic model of C vs. A . After excluding studies deviating from HWE Of the 26 studies investigating the association between the late ORs . By poolIL10 −592 C allele was associated with decreased SLE risk among Asians . The associations were not found among Caucasians under any genetic model.In the subgroup analyses by ethnicity, the results showed that only under the genetic model of CC+CA vs. AA the IL10 −592C/A polymorphism and SLE susceptibility . Excluding the study by Sobkowiak IL10 −3575T/A polymorphism and SLE susceptibility. The meta-analyses showed no association under any genetic model. The I2 statistic showed that the between-study heterogeneity was not apparent.There were four studies investigating the association between the IL10 −2763C/A polymorphism and SLE susceptibility. The meta-analyses showed that the IL10 −2763 C allele was associated with increased SLE risk . Further analysis showed that the study by Gibson contributed to this association. In this study, the authors studied African Americans.There were three studies investigating the association between the IL10 gene, only rs3024505 was associated with SLE among Caucasians .For other SNPs in the IL-10 is a potent stimulator of B cells in one way and a strong inhibitor of antigen-presenting cells and T cells in another way. Therefore, it plays an important role in immune and inflammatory process and aberrant expression of IL-10 contributes to the development of autoimmune diseases IL-10.G microsatellites is associated with SLE IL-10.G microsatellites and SLE. In addition, we found an association between the CA21 allele and SLE in Asian patients with between-study heterogeneity. However, it should be noticed that different alleles in the IL-10.G microsatellites have been linked with SLE risk in different studies. Ethnicity and patient heterogeneity may explain it. The allele distributions of the IL-10.G microsatellites are often different among different populations; some subgroup patients such as patients with anti-Sm antibodies or with nephritis tend to correlate with certain IL-10.G alleles, while their distributions are different among different studies IL-10.G microsatellites are markers of disease susceptibility due to linkage disequilibrium with some causal variation.Previous meta-analysis has found that the CA23 allele of the IL-10 −1082 G/A polymorphisms and SLE among Caucasians, because the results were consistent under three genetic models  without between-study heterogeneity and insensitive to HWE status in control groups. An earlier meta-analysis, because of very limited studies included, failed to result in a positive finding IL-10 −1082 G/A polymorphisms among Asians, but the numbers of included Asian studies were smaller than ours IL-10 −1082G allele was associated with higher IL-10 production following ConA stimulation of human peripheral blood lymphocytes in vitroIL-10 −1082 G/A polymorphisms have an effect on IL-10 production and thus influencing disease susceptibility. The IL-10 −1082 G/A polymorphisms may also be a marker of disease susceptibility due to linkage disequilibrium.This meta-analysis showed a relative solid association between the IL-10 gene. Thus, among Caucasians our meta-analysis produced consistent findings for the IL-10 −819 C/T and −592 C/A. But for studies from Asia, 4 of them did not show a complete linkage disequilibrium at the two positions IL-10 −592 C/A polymorphisms were significantly associated with SLE under the genetic model of CC+CA vs. AA and showed a trend of association but not statistically significant under other models. This may contribute to positive findings from overall analyses of the IL-10 −592 C/A polymorphisms when excluding studies deviating from HWE. Eskdale et al. reported that the C allele at −592 of the IL-10 gene or its associated haplotype was related to increased production of IL-10 by whole blood or PBMCs IL-10 −592 C/A polymorphisms All studies from Europe showed a complete linkage disequilibrium at positions −819 and −592 in the IL10 −1082/−819/−592 haplotypes in included studies. Overall meta-analysis showed that the GCC haplotype was associated with increased and the ACC haplotype with decreased SLE susceptibility and the results were sensitive to ethnicity and HWE status in control groups. These findings were similar with a recent meta-analysis IL-10 gene, similar findings should be yielded from the analysis of the GCC haplotype and the IL-10 −1082 G/A polymorphisms. This can be seen in our present meta-analysis. Because of the almost complete linkage disequilibrium, functional findings about the IL-10 −1082 G/A polymorphisms are suitable for the GCC haplotype.Because of linkage disequilibrium, GCC, ACC and ATA were the only three haplotypes or account for the vast majority of the This meta-analysis involving 7948 cases and 11866 controls used an exhaustive search strategy in recommended databases without language restrictions IL-10 −819 C/T and −592 C/A polymorphisms. This may be due to reporting bias, other biases or genuine heterogeneity, and it may be difficult to determine which is the case IL10 −3575T/A and −2763C/A, relevant studies are quite few; there were also very limited studies conducted among black people; more studies needed to duplicate the association of rs3024505 with SLE. Fourth, to our knowledge, the SNPs that are related with SLE in this study have not been highlighted in recent GWAS focused on SLE except the SNP rs3024505. It is common that findings are different from candidate gene studies and GWAS studies. The reasons are currently hard to explain. Some possible reasons include: variation in demographic profile of controls, linkage disequilibrium in different populations, variation in accuracy of genotyping methods, false discovery, and confounding factors.Some caveats need to be noted regarding the present study. First, there was significant heterogeneity among included studies, especially among studies from Asia. Pan et al. reported that Chinese gene-disease association studies often have more heterogeneity than others IL-10.G microsatellites, the IL-10 −1082G/A polymorphism and its associated haplotype of GCC are associated with SLE susceptibility among Caucasians and the CA21 allele of the IL-10.G microsatellites, the IL-10 −1082G/A and −592 C/A polymorphisms and their associated haplotype of GCC may be associated with SLE susceptibility among Asians. It is worthwhile to note that this is the first time to report an association between the CA27 allele of the IL-10.G microsatellites and SLE among Caucasians. Further studies are needed to confirm these findings. More studies are also needed to duplicate the associations between SLE and some rarely studied SNPs such as rs3024505.In summary, this meta-analysis showed that the CA27 allele of the Methods S1Search strategies.(DOCX)Click here for additional data file.Methods S2Checklist to confirm compliance with PRISMA guidelines for systematic reviews and meta-analyses.(DOCX)Click here for additional data file.Reference S1List of included studies in this meta-analysis.(DOCX)Click here for additional data file.


X-ray repair cross-complementing group 1 (XRCC1) is one of the DNA repair genes encoding a scaffolding protein that participate in base excision repair (BER) pathway. However, studies on the association between polymorphisms in this gene and glioma have yielded conflicting results. This meta-analysis was performed to derive a more precise estimation between XRCC1 polymorphisms  and glioma risk.Data were collected from several electronic databases, with the last search up to November 28, 2012. Meta-analysis was performed by critically reviewing 9 studies for Arg399Gln polymorphism (3146 cases and 4296 controls), 4 studies for Arg194Trp polymorphism (2557 cases and 4347 controls), and 4 studies for Arg280His polymorphism (1936 cases and 2895 controls). All of the statistical analyses were performed using the software programs STATA (version 11.0).The combined results showed that Arg399Gln polymorphism was significantly associated with glioma risk , whereas Arg194Trp/Arg280His polymorphisms were all not significantly associated with glioma risk. As for ethnicity, Arg399Gln polymorphism was associated with increased risk of glioma among Asians , but not among Caucasians. Stratified analyses by histological subtype indicated that the Gln allele of Arg399Gln polymorphism showed borderline association with the risk of glioblastoma among Caucasians. However, no evidence was observed in subgroup analyses for Arg194Trp/Arg280His polymorphisms.Our meta-analysis suggested that Arg399Gln polymorphism was associated with increased risk of glioma among Asians and borderline increased risk for glioblastoma among Caucasians, whereas Arg194Trp/Arg280His polymorphisms might have no influence on the susceptibility of glioma in different ethnicities. Gliomas are the most common type of primary brain tumors, including astrocytomas, oligodendrogliomas, oligoastrocytomas, and glioblastoma, which can be classified into four clinical grades  based on histopathological characteristics and biological behaviors. Among them, the glioblastoma (GBM) is the most frequent and malignant histologic type with worse prognosis DNA damage or reduced DNA repair capacity is viewed as an important mechanism in genetic instability and carcinogenesis caused by ionizing radiation and environmental chemical agents. There are four major DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and double strand break repair (DSBR) A comprehensive literature search was performed using PubMed and EMBASE to identify studies that evaluated the association between XRCC1 polymorphisms and the risk of glioma up to November 28, 2012 with the following terms and keywords: (XRCC1 or ‘X-ray repair cross-complementation group 1’ or ‘DNA repair gene’) and (polymorphism or variant or variation) and (glioma or ‘brain tumor’). The search was limited to human studies. Additional studies were identified by hand searching references in original articles and review articles. The following criteria were used for the study selection: 1) a case–control study evaluating at least one polymorphism in the XRCC1 gene; 2) studies with full text articles; 3) sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI); 4) genotype distribution of control population must be in Hardy–Weinberg equilibrium (HWE); 5) no overlapping data. If studies had the same or overlapping data, only the largest study should be included in the final analysis.Information was carefully extracted from all the eligible studies independently by three investigators according to the selection criteria listed above. The following data were collected from each study: first author, publication year, country, racial descent , source of controls, genotyping method, numbers of cases and controls, genotype frequency of cases and controls, and the result of Hardy–Weinberg equilibrium test. For conflicting evaluation, a consensus was reached by discussion. We did not define any minimum number of patients for inclusion in our meta-analysis.http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl) was applied to determine if observed frequencies of genotypes in controls conformed to HWE (P<0.05 was considered significant). Crude ORs together with their corresponding 95% CIs were used to assess the strength of association between these three XRCC1 polymorphisms  and glioma risk for each study. The pooled ORs were performed for additive model , codominant model , dominant model (aa+Aa versus AA), recessive model (aa versus Aa+AA) respectively. Heterogeneity assumption was checked by a chi-square-based Q test I2 statistics was calculated to quantify the proportion of the total variation across studies due to heterogeneity p-value of >0.05 for the Q-test indicated a lack of heterogeneity among studies, so that the pooled OR estimate of each study was calculated by the fixed-effects model (the Mantel–Haenszel method) A Chi-square test using a web-based program Click here for additional data file.


IL1-RN) and a polymorphism in exon 5 of IL1B  have been suggested in predisposition to cancer risk. However, studies have shown inconsistent results. To validate any association, a meta-analysis was performed with 14,854 cases and 19,337 controls from 71 published case–control studies for IL1-RN VNTR and 33 eligible studies contained 7,847 cases and 8917 controls for IL1B +3954. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from comparisons to assess the strength of the association. There was significant association between the IL1-RN VNTR polymorphism and the risk of cancer for any overall comparison. Furthermore, cancer type stratification analysis revealed that there were significantly increased risks of gastric cancer, bladder cancer and other cancer groups. Infection status analysis indicated that the H. pylori or HBV/HCV infection and IL1-RN VNTR genotypes were independent factors for developing gastric or hepatocellular cancers. In addition, a borderline significant association was observed between IL1B+3954 polymorphism and the increased cancer risk. Although some modest bias could not be eliminated, this meta-analysis suggested that the IL1-RN VNTR polymorphisms may contribute to genetic susceptibility to gastric cancer. More studies are needed to further evaluate the role of the IL1B+3954 polymorphism in the etiology of cancer.IL1 receptor antagonist (IL1RA) and IL1beta (IL1β), members of the pro-inflammatory cytokine interleukin-1 (IL1) family, play a potential role against infection and in the pathogenesis of cancers. The variable number of tandem repeats (VNTR) polymorphism in the second intron of the IL1 receptor antagonist gene ( IL1A, IL1B and IL1-RN, which encode IL1α, IL1β and IL1RA respectively. IL1B may play an essential role in the carcinogenic process. Several IL1B gene single nucleotide polymorphisms have been described to be associated with cancers to date IL1B was a low-penetrance protective factor for the development of cancer IL1B has been found to affect IL1B gene expression IL1-RN gene, there exists a variable number of tandem repeats (VNTR) with an 86 base pair nucleotide sequence as its repeating element. This region contains three potential protein binding sites: an interferon α silencer A, an interferon β silencer B and an acute phase response element, and thus may be of functional relevance IL1-RN. Another study revealed that IL1-RN VNTR genotypes were highly correlated with cellular function. The IL-1RN alleles were coded as previously described: allele 1, four repeats; allele 2, two repeats; allele 3, five repeats; allele 4, three repeats and allele 5, six repeats. The IL-1RN alleles were further divided into two categories: long genotype  and short genotype . The genotypes were classified as LL, 2L, and 22 Interleukins (ILs) are pro-inflammatory cytokines produced by monocytes, macrophages and epithelial cells. The interleukin-1 (IL1) family consists of the cytokines IL1alpha (IL1α), IL1beta (IL1β) and a specific receptor antagonist (IL1RA) IL1B+3954 and IL1-RN polymorphism and cancers of different tissue origins, but inconsistent results have been obtained. These inconsistent findings might be caused by a range of factors such as heterogeneity by cancer subtype, limited sample size, and gene-environment interactions. To further assess and validate the association of the IL1B +3954 and IL1-RN VNTR polymorphism with cancer risk, a comprehensive review and analysis of published data from different study groups is urgently needed. In this study, we have extensively reviewed literature and performed a meta-analysis based on all eligible case-control published data to evaluate the association between the IL1B+3954 and IL1-RN VNTR polymorphism and cancer susceptibility.A large number of genetic susceptibility studies have been carried out to investigate the associations between the IL1B+3954 and IL1-RN VNTR polymorphism and cancer risk, (ii) it was a case–control designed study and (iii) it contained available genotype frequencies  by using the key words ‘interleukin-1 receptor antagonist’, ‘IL1’, ‘polymorphism’, or ‘cancer’. The search was limited to English language papers and human subject studies. In addition, studies were identified by a manual search of the reference lists of reviews and retrieved studies. When more than one of the same or overlapping populations by different investigators or overlapping data by the same authors were found, only the most recent or complete study was used for this meta-analysis. Studies, regardless of sample size, were included if they met the following criteria: (i) the study was of the quencies .IL1-RN VNTR subgroup analysis.Two individuals (Ying Zhang and Changming Liu) extracted all data independently complying with the selection criteria. For each study, the following characteristics were extracted: the first author’s last name, year of publication, country of origin, ethnicity, matching numbers of genotyped cases and controls, the source of control groups , genotyping methods and cancer type. Different ethnic descents were categorized as Caucasian, Asian or mixed, which included more than one ethnic descent. One study included the information for genotypes of LL/2L and 22, without data for LL and 2L genotypes, so we were only able to calculate the OR for the comparison between alleles 2 and L IL1B+3954 and IL1-RN VNTR polymorphisms were tested for associations with cancer susceptibility based on different genetic models. The meta-analysis examined the overall association of the IL1B+3954 and IL1-RN VNTR polymorphism with the risk of cancer measured by odds ratios (ORs) with 95% confidence intervals (CIs). To contrast the wild-type homozygote (IL1B+3954-CC or IL1-RN-L/L), we first estimated the risks of the IL1B+3954 -CT, -TT and IL1-RN -2/L, -2/2 genotypes on cancers, then evaluated the risk of cancer under a dominant model. In addition, recessive model associations were also estimated . Stratified analyses were also performed by ethnicity , cancer types , moreover, subgroup analysis was carried by infection status for IL1-RN VNTR polymorphism.The The statistical significance of the pooled OR was determined with the Z test, a P value of<0.05 was considered significant. The heterogeneity between studies was evaluated by the chi-square based Q statistical test All statistical tests for this meta-analysis were performed with STATA version 10.0 , and SAS .IL1-RN VNTR polymorphism, a total of 71 eligible studies met the preset inclusion criteria, in which 14,854 cases and 19,337 controls were included for the pooled analysis  was performed in most studies, direct sequencing was used by two studies helicobacter pylori (H. pylori), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection status.For analysis . All stuIL1B+3954 polymorphism, 33 eligible studies contained 7,847 cases and 8,917 controls were enrolled for the pooled risk analysis  among Asian controls, which was significantly lower than that in Caucasian controls , as shown in Pheterogeneity<0.001), other cancer group . In the genotypic analysis, significant associations were found in gastric cancer , other cancer group . In contrast to the increased risk of the IL1-RN polymorphism for cancers, a decreased risk was also observed in breast cancer . Significant increased risk was also observed in the ethnicities subgroup analysis. For Asian ethnicity, there was a significant association in the comparison of 2L versus LL , 22+2L versus LL  and allele 2 versus L . A significant association was also observed in the comparison of 22+2L versus LL  and 2 versus L  in Caucasian ethnicity. In addition, two studies with mixed ethnicity data revealed increased risk using the comparisons of 2L versus LL and 22+2L versus LL . Subgroup analysis determined by the source of control revealed a significant association between the IL1-RN VNTR polymorphism and cancer risk, with the exception of hospital based controls for the comparison of 22 versus LL and population based controls for the comparison LL+2L versus 22 summarized in For IL1B+3954 polymorphism, borderline significant risk associations were observed in the pooled analysis for the comparison of TT versus CC , TT+CT versus CC  and TT versus CT+CC In addition, subgroup analysis revealed the similarly associations in the population based studies . Cancer type subgroup analysis revealed significant association for oral cancer , in contrast, significant association was observed in the other cancers subgroup summarized in For IL1-RN VNTR genotype among cases and infection-matched controls was available in twenty studies that investigated gastric cancer infected by H. pylori and hepatocellular cancer infected by the hepatitis B or hepatitis C virus. Carriers of the 2 allele had higher cancer risk than those with the IL1-RN- L allele among gastric cancer studies, and the subgroup analysis results revealed that the L allele is a risk of gastric cancer independent of H.pylori infection. However, there was no association between the IL1-RN VNTR polymorphism and cancer risk in hepatocellular cancer studies as illustrated in The genotype distribution of the IL1-RN VNTR and IL1B+3954 polymorphism, there was significant heterogeneity across the studies. For this, the source of heterogeneity was explored for the heterozygote comparison (CT versus CC) by cancer type, ethnicity and source of controls. Cancer type , ethnicity  and source of controls  contributed to the heterogeneity. In similarly, for IL1-RN VNTR polymorphism, Cancer type  but not ethnicity  or source of controls  contributed substantially to that heterogeneity.For IL1-RN VNTR and IL1B+3954, respectively. The heterogeneity was decreased when these studies were removed .Sensitivity analysis revealed that ten IL1-RN VNTR: t = 1.84, P = 0.071 for 2L versus LL, IL1B+3954: t = 0.82, P = 0.420 for CT versus CC, Begg’s funnel plot and Egger’s test were performed to assess the publication bias of the currently available literature. The shape of the funnel plots did not reveal any evidence for obvious asymmetry in all comparison models. Then, the Egger’s test was used to provide statistical evidence for funnel plot symmetry. The results still did not show any evidence of publication bias . More studies on large-scale gene-gene and gene-environment interactions are needed to further evaluate and elucidate the human genetic predisposition to various cancers.Although meta-analyses are robust, our study still has some limitations. First, most of the selected studies focused on gastric cancer. The relatively small sample size of studies in other stratified groups may lead to reduced statistical power. Second, although all eligible studies were summarized, the total sample size might have not been enough to make a convincing conclusion. When stratified analysis of tumor type, ethnicity or infection status was performed, the number of each subgroup was smaller. Third, our meta-analysis included no evaluation of potential gene-gene interactions and limited gene-environment interactions due to the lack of relevant published data. Because cancer is a complex disease, genetic factors may play a limited impact on the pathogenesis of cancers. In the results of our present meta-analysis, the IL1-RN VNTR polymorphism may contribute to genetic susceptibility to gastric cancer, which is closely related to the immunological response. IL1B+3954 has a borderline significant association with increased cancer risk. More studies are needed to further evaluate the role of the IL1B+3954 polymorphism in the etiology of cancer.In conclusion, this meta-analysis suggests that the Figure S1Process of study selection of case–control studies.(TIF)Click here for additional data file.Table S1IL1-RN VNTR in present meta-analysis study.Summary of published studies included for (DOC)Click here for additional data file.Table S2IL1B+3954 in present meta-analysis study.Summary of published studies included for (DOC)Click here for additional data file.


Prospective cohort studies in relation to the associations between n-3 polyunsaturated fatty acids (PUFA) and risk of type 2 diabetes (T2D) were inconsistent. Differences in tissue n-3 PUFA compositions in subjects with and without T2D were also inconsistent in both cohort and case-control studies. We conducted a systematic review and meta-analysis of prospective cohort studies to examine the associations of fish and n-3 PUFA intake with T2D risk. The differences in tissue n-3 PUFA compositions in subjects with and without T2D were investigated based on cohort and case-control studies.PubMed, Embase, Cochrane library, China National Knowledge Infrastructure (CNKI) and Chinese VIP database up to January 2012 was used to identify relevant studies, and reference lists from retrieved studies were reviewed. Two authors independently extracted the data. Random-effects models were used to pool the summary relative risk (RR). Twenty-four studies including 24,509 T2D patients and 545,275 participants were identified. For cohort studies, the summary RR of T2D for the highest vs lowest categories of total fish, marine n-3 PUFA and alpha-linolenic acid intake was 1.07 , 1.07  and 0.93 , respectively. Subgroup analyses indicated that summary RR (highest vs lowest category) of T2D for fish and marine n-3 PUFA intake was 0.89  and 0.87  for Asian populations, and 1.20  and 1.16  for Western populations. Asian subjects with T2D had significantly lower tissue compositions of C22∶6n-3  and total n-3 PUFA  compared with those without T2D.This systematic review and meta-analysis provides evidence that marine n-3 PUFA have beneficial effects on the prevention of T2D in Asian populations. Type 2 diabetes (T2D) is one of the most common chronic diseases in the world, leading to a huge economic burden for society Tissue (plasma/serum/erythrocytes) n-3 PUFA compositions were reported to be significantly lower in subjects with T2D compared with control subjects in case-control studies Therefore, the aim of the present meta-analysis was to investigate the associations of fish and n-3 PUFA intake with risk of T2D based on prospective cohort studies. The differences of tissue (plasma/serum/erythrocytes) n-3 PUFA compositions in subjects with and without T2D were also investigated based on prospective cohort and case-control studies. Stratified analyses were conducted to examine sources of heterogeneity.http://www.prisma-statement.org; Our report followed the Meta-analysis of Observational Studies in Epidemiology Guidelines Two authors (JZ and TH) independently conducted the search and discrepancies were resolved through group discussion. To investigate the associations of fish and n-3 PUFA intake with risk of T2D, the inclusion criteria were: 1) prospective cohort study design; 2) the exposure of interest was dietary intake of fish, fatty fish, shellfish, n-3 PUFA, marine n-3 PUFA or alpha-linolenic acid ; 3) the endpoint of interest was T2D incidence; 4) relative risk (RR) or hazard ratio (HR) with the corresponding 95% confidence interval (CI) of T2D for each category of fish or n-3 PUFA intake were provided; and 5) if the same population or cohort was duplicated, the most recent and complete study was included. To investigate the differences in tissue (plasma/serum/erythrocytes) n-3 PUFA compositions in subjects with and without T2D, the inclusion criteria were: 1) prospective cohort or case-control study design; 2) tissue compositions of C22∶6n-3, C20∶5n-3, C18∶3n-3 or total n-3 PUFA in subjects with and without T2D were provided; 3) both the cases and controls in each study were from the same population. The exclusion criteria were: studies with cross-sectional, ecologic or intervention study design; duplicate studies; studies without detailed risk estimates of T2D for dietary fish or n-3 PUFA intake, or without tissue n-3 PUFA compositions in T2D subjects and controls.The following information was extracted from the included studies: first author’s name, year of publication, study region and population, duration of follow-up, age of subjects, gender, number of events, participants and person-years for the entire study and for each fish or n-3 PUFA intake category, adjusted covariates, method of dietary assessment, RR or HR with their 95% CIs for each fish or n-3 PUFA intake category, tissue compositions of C22∶6n-3, C20∶5n-3, C18∶3n-3 and total n-3 PUFA in subjects with and without T2D. The greatest degree of adjusted RR or HR from each cohort study was extracted.RR was taken as the common risk estimate for the associations between fish and n-3 PUFA intake and T2D risk. HR was considered as RR directly. RR from each study was firstly transformed to their natural logarithm and corresponding 95% CIs were used to calculate standard errors. DerSimonian and Laird random-effects model, which took both within- and between-study variation into consideration was used to combine the RRs and they were weighted by the inverse of their variances. The differences in tissue n-3 PUFA compositions in subjects with and without T2D were also analyzed as standardized mean difference (SMD) by pooling the data from case-control and cohort studies.To further examine the relationship between fish intake and T2D risk, total fish consumption was standardized and categorized into four groups: 1) high (>5 servings/wk); 2) moderate (2–4 servings/wk); 3) low (1 serving/wk); and 4) reference group (<1 serving/wk or 1–3 servings/wk), if both <1 serving/wk and 1–3 servings/wk were available in a study, <1 serving/wk was chosen as reference group. Each RR from included studies was assigned into a corresponding standardized group. If more than one fish intake category fell into the same standardized group, the RRs were combined for further analysis. One portion or serving of fish was regarded as 105 g as described previously Dose-response analyses for total fish and marine n-3 PUFA intake were conducted according to Greenland and Longnecher P<0.1) and 2I statistics 2I values of 25%, 50% and 75% correspond to cut-off points for low, moderate and high degrees of heterogeneity. Subgroup analyses were conducted to examine the sources of heterogeneity. Influence of individual study on the overall risk estimate or effect size was examined by sensitivity analysis in which one study at a time was excluded. Begg’s funnel plot and Egger’s regression test (significant at P<0.1) were used to evaluate publication bias. All the analyses were performed by using STATA version 11 .Statistical heterogeneity was assessed with the Q . No publication bias was observed from Begg’s funnel plot and Egger’s test (P = 0.60).There was no significant association between total fish intake (highest vs lowest category) and risk of T2D  . High deThe summary RR of T2D was 1.03 , 1.06 , and 1.05  for high (>5 per wk), moderate (2–4 per wk), and low (1 per wk) fish intake respectively . No doseThe summary risk estimates for the highest vs lowest categories of fatty fish, lean fish and shellfish intake were 0.91 , 1.03  and 0.96  respectively. No publication bias was observed for all the analyses of fatty fish, lean fish and shellfish intake (data not shown).P for heterogeneity <0.001, 2I = 80.8). Overall, no publication bias was observed from Begg’s funnel plot and Egger’s test (P = 0.338). No significant dose-response association between marine n-3 PUFA and risk of T2D was found .There was no significant association between marine n-3 PUFA intake and risk of T2D  . High deThe pooled RR of T2D was 0.93  for the highest vs lowest C18∶3n-3 intake . No publSubjects with T2D had significantly lower tissue compositions of C18∶3n-3  compared with subjects without T2D. No publication bias was observed (data not shown). No significant differences were observed for the other n-3 PUFA compositions .Subgroup analyses  revealed) showed that Asian subjects with T2D compared with those without T2D, tissue compositions of C22∶6n-3  and total n-3 PUFA  were significantly lower.  associated with T2D only in the GWAS of European populations, while genetic variants at some others genes  associated with T2D only in the GWAS of East Asian populations PPARG associated with T2D only in the GWAS of Europeans, but not East Asians PPARG can be regulated by n-3 PUFA PPARG variants to influence T2D risk in the European populations, but not in the East Asian populations. Therefore, as most of our included Asian studies are from East Asia, it is reasonable to postulate that n-3 PUFA intake may interact with a number of T2D-related genes for the risk of T2D, and there may be a different interaction pattern for n-3 PUFA and the T2D-related genes for the risk of T2D in the East Asian and Caucasian populations et al. found that plasma n-3 PUFA were inversely associated with insulin sensitivity and metabolic syndrome in Chinese populations One possible explanation was the influence of genetics on incidence of T2D as suggested by the high levels of differentiation between different populations for the ensemble of T2D loci In addition to the influence of gene-diet interaction, differences in dietary patterns between Asian and Western populations might be another explanation for the inconsistent findings. Western dietary pattern is characterized by high intakes of sugar, red meat and fried food; while Asian dietary pattern, especially Chinese and Japanese, also known as a prudent dietary pattern, includes high intake of fruit, vegetable, fish and tofu. Western dietary pattern score was positively associated with risk of T2D, while a prudent dietary pattern score was inversely associated with risk of T2D The potential benefit of marine n-3 PUFA is their incorporation into cell membranes, subsequently increasing insulin sensitivity The effects of fish consumption on T2D were highly consistent with that of marine n-3 PUFA in the present meta-analysis. Fish are rich sources of marine n-3 PUFA and the effects of fish on T2D might be attributed to the effects of C22∶6n-3 and C20∶5n-3. However, oily fish and lean fish, which contained quite different concentrations of C22∶6n-3 and C20∶5n-3, did not exert significantly different effects on risk of T2D compared with each other, and with total fish consumption in the present study; it might be that the study number for fatty fish and lean fish intake with T2D risk was small In contrast to marine n-3 PUFA, only a few cohort studies reported the association between C18∶3n-3 intake and T2D risk; further, C18∶3n-3 was lower in T2D subjects compared with controls, especially in Western populations. It might be that C18∶3n-3, the vegetable fatty acid, might affect the risk of T2D through different mechanisms compared with marine n-3 PUFA, which merits further investigations There are several strengths in the present study. First, large sample size of the included studies makes this meta-analysis more powerful to examine the associations between fish and n-3 PUFA intake and risk of T2D than any individual study. Second, although randomized controlled trials are the best way to achieve causal inference, however, there is no data for the association of fish and n-3 PUFA intake with T2D risk available in the literatures. Therefore, we systematic reviewed results from available cohort studies, and prospective nature of the included cohort studies (fish and marine n-3 PUFAs intake and T2D risk) makes the results less likely to be affected by recall and selection biases. Third, both the associations of marine and non-marine n-3 PUFA with risk of T2D were examined; and the associations of total fish, fatty fish, lean fish and shellfish intake with risk of T2D were all analyzed in this study, thus giving a relatively complete view of the current available evidence in relation to the associations of fish, n-3 PUFA intake with risk of T2D. Lastly, tissue n-3 PUFA compositions in subjects with and without T2D were compared, which supported the results from cohort studies.Some limitations presented in this meta-analysis. First, classifications of fish and n-3 PUFA intake amounts were inconsistent among studies, which might have influenced the results. However, we used RRs of the highest vs lowest categories of fish or n-3 PUFA intake, which might reduce the bias caused by misclassification. Second, observational studies could not avoid residual confounders. Potential confounders always existed although most of the included studies had adjusted a wide range of confounders.In conclusion, this systematic review and meta-analysis provided evidence that marine n-3 PUFA consumption had protective associations with risk of T2D in Asian populations, but was positively associated with risk of T2D in Western populations. T2D subjects in Asian but not in Western countries had lower tissue C22∶6n-3 and total n-3 PUFA compositions than controls. These findings have important public health implications. The prevalence of T2D has been steadily increasing around the world; dietary marine n-3 PUFA intake has proven to be protective for cardiovascular disease, but its effects on T2D risk were inconsistent among different populations. Influences of genetics and gene-diet interaction on T2D within different populations should be further explored to understand the association between marine n-3 PUFA intake and risk of T2D.Text S1PRISMA checklist.(DOC)Click here for additional data file.Text S2Study protocol for systematic review and meta-analysis to determine the effects of n-3 polyunsaturated fatty acids on risk of type 2 diabetes.(DOC)Click here for additional data file.


Although the genetic basis of androgenic alopecia has been clearly established, little is known about its non-genetic causes, such as environmental and lifestyle factors.This study investigated blood and urine heavy metals concentrations, environmental exposure factors, personal behaviors, dietary intakes and the genotypes of related susceptibility genes in patients with androgenic alopecia (AGA).2 and accuracy tests were conducted to help establish an optimal model.Age, AGA level, residence area, work hours, sleep patterns, cigarette usage, alcohol consumption, betel nut usage, hair treatments, eating habits, body heavy metals concentrations and rs1998076, rs913063, rs1160312 and rs201571 SNP genotype data were collected from 354 men. Logistic regression analysis was performed to examine whether any of the factors displayed odds ratios (ORs) indicating association with moderate to severe AGA (≧IV). Subsequently, Hosmer-Lemeshow, Nagelkerke R2 (0.59), accuracy test (0.816) and area under the curve  analysis.Moderate to severe AGA was associated with the AA genotype of rs1160312 , blood vanadium concentration , and regular consumption of soy bean drinks , after adjustment for age. The results were corroborated by the Hosmer-Lemeshow test (P = 0.73), Nagelkerke RBlood vanadium and frequent soy bean drink consumption may provide protect effects against AGA. Accordingly, blood vanadium concentrations, the AA genotype of rs1160312 and frequent consumption of soy bean drinks are associated with AGA. The incidence of androgenic alopecia (AGA) is increasing, while the age of onset of AGA continues to decrease. Studies have associated AGA with a variety of diseases, such as coronary heart disease et al. identified a baldness susceptibility gene that increases the risk of AGA six-fold; the variance explained by this allele was reported to be 13.7% et al.Many studies have been devoted to the genetic and androgen-related aspects of AGA AR gene on the X chromosome and two autosomal loci, 3q26 et al. observed that variants in the 20p11 locus and the AR gene are common among Europeans and that men with at least one risk allele (20p11.22 or AR) at either locus have a seven-fold greater probability of developing AGA than those without either risk allele et al. also showed that the 20p11 locus is associated with early-onset AGA To date, three AGA susceptibility genes have been identified: the et al. discovered that DNA short tandem repeats on chromosome 3  are related to AGA et alSRY increases with the severity of baldness. Therefore, we attempted to investigate two single nucleotide polymorphisms (SNPs) within the SRY gene.In addition, Hillmer Although a strong genetic basis for AGA has been established, little is known about its non-genetic causes, such as environmental and dietary factors. This study investigated the bodily heavy metals concentrations, dietary habits and genotypes of related susceptibility genes in patients with AGA.It has been suggested that air pollution may lead to the over-accumulation of certain heavy metals in the scalp, resulting in hair loss Smoking also affects the development of AGA because the genotoxic compounds in cigarettes may damage the DNA in hair follicles and subsequently cause microvascular poisoning in hair papillae Despite the discovery of genes associated with this disorder, many factors contributing to the variable levels of AGA have yet to be elucidated. To date, no study has comprehensively examined many of the potential AGA-associated factors, such as dietary and body concentrations of heavy metals. Thus, we attempted to assess the association between the physiological concentrations of heavy metals, dietary factors and susceptibility genes in men with AGA.The research subjects were men from 35 to 65 years of age who had lived in the districts of Dadu, Longjing and Shigang in Taichung for at least 5 consecutive years. Age and relocation time were used to divide individuals who met these criteria into three age groups . Subsequently, 13 villages were selected as research sites based on their registered permanent residents; each village contained 40 individuals in each of the three age groups. A total of 1560 men were examined.Consent letters and survey forms were mailed to the subjects from the sample list, and appointments were arranged at local health centers. The signed consent letters were collected at these appointments. A total of 354 men agreed to participate in the study. A physical examination, specimen collection and photographic documentation of the scalp were performed by nurses in these public health centers.A matched case-control study was conducted with controls recruited from the communities in the previously defined districts of Dadu, Longjing and Shigang in Taichung of central Taiwan. Eligibility was restricted to locally registered residents who had lived in the selected areas for more than five consecutive years and who were between 35 and 64 years old.Subjects were recruited from five villages within the Longjing and Dadu townships. The reference group was recruited from the two villages of the Shihgang Township, an area located in northeast Taichung County that is free of industrial pollution. Eligible subjects were registered local residents who had lived in the selected areas for more than five consecutive years and who were between 35 and 64 years old. A total of 1440 subjects were randomly selected from each age group , gender  and village, i.e., a total of 12 subgroups. This study focused on AGA in men. A total of 354 men agreed to participate in the study, for a response rate of 49.2% (354/720); 277 of the subjects were from the exposed area, and 77 were from the reference area.This study was approved by the institutional review board at the Tri-Service General Hospital in Taipei, Taiwan. Study consent letters and questionnaires were mailed to the subjects from the sample list, and appointments were arranged at local health centers. All the participants signed informed consent waivers prior to study enrollment. The examination, specimen collection and photographic documentation of the scalp were performed at the public health centers.At the beginning of the study, we mailed a self-administered questionnaire to the participants. The questionnaire gathered information about personal characteristics and lifestyle information, such as age, education, smoking habits, alcohol consumption, betel nut usage, work hours, sleep patterns, hair treatments, disease history, and eating habits. Subjects were asked to collect a first void urine sample using a 100 ml polyethylene container on the morning of their appointment. The subjects brought their survey questionnaires and urine samples to the public health centers. The intra-class correlation of dietary intake from 65 studies was 0.9 for two food frequency questionnaires (FFQ) administered 1 month apart, with correlations of 0.4 to 0.8 for various nutrients 2 EDTA tubes  to evaluate heavy metal concentrations or (2) EDTA tubes  to extract DNA. The blood collection tubes were transported in a cooler and stored at 4°C during shipping to the laboratory. The blood samples were divided into aliquots for heavy metal analyses. For the DNA extraction, the EDTA-containing whole blood was centrifuged for 15 min, and the resulting buffy coat containing the white blood cells was subjected to genomic DNA extraction. SNP genotyping was performed using the ABI TaqMan® system. The degree of AGA was evaluated based on the Hamilton-Norwood scale by specialists at the public health centers.The blood samples were collected by venipuncture from the forearm in either (1) trace element ket al. and Ellis et al.) and rs6625163  located within Xq12–Xq13; rs1158928 (the highest odds ratio) located within Xq11–Xq12; rs1998076 , rs1160312 , rs201571  and rs913063 (used to verify an r2 of 1 between this locus and rs1160312) located within 20p11.1–20p11.2. No polymorphisms in rs925391, rs10521339, rs6625163, rs1158928, rs6152 or rs2534636 were found among Asians. However, five of the variants, rs1998076, rs913063, rs1160312, rs201571 and rs11575897, were found to be polymorphic among Asians. Thus, the latter five SNPs were used for the genotyping tests.The keyword “androgenic alopecia” was used to search the Online Mendelian Inheritance in Man (OMIM) database for human studies, yielding three accession numbers: 109200, 300710 and 612421. These accession numbers were used in a literature search, which identified AGA-associated genes located on chromosomes X Inductively coupled plasma mass spectrometry (ICP-MS)  was used to measure the concentrations of heavy metals  in the blood and urine samples.The recovery efficiencies from urine samples were determined by spiking a known quantity of a trace element (NIST SRM ®2670a) into a urine sample and following the same experimental procedure used for the treatment of urine samples. The recoveries were as follows: V, 102%; Mn, 103%; Co, 104%; Cu, 102%; Zn, 94%; As, 104%; Cd, 104%; Pb, 104%; Ni, 105%; and Cr, 99%. The blank tests for metals were performed using the same procedure used in the recovery efficiency tests but without adding the known standard solution. The limits of detection were as follows (in µg/L): V, 0.028; Mn, 0.027; Co, 0.004; Cu, 0.025; Zn, 0.075; As, 0.027; Cd, 0.017; Pb, 0.026; Ni, 0.032; and Cr, 0.037. At these limits, the signal-to-noise ratio was 3.The recovery efficiencies from blood samples were determined by spiking a known quantity of trace elements (Seronorm™) into a blood sample and following the same experimental procedure used for the treatment of the blood samples. The recoveries were as follows: V, 104%; Mn, 101%; Co, 97%; Cu, 95%; Zn, 103%; As, 96%; Cd, 98%; Pb, 100%; Ni, 97%; and Cr, 104%. The limits of detection were as follows (in µg/L): V, 0.051; Mn, 0.018; Co, 0.006; Cu, 0.047; Zn, 0.032; As, 0.039; Cd, 0.013; Pb, 0.012; Ni, 0.019; and Cr, 0.032. At these limits, the signal-to-noise ratio was 3.The analyses of the blanks, including field blanks and lab blanks, revealed no significant contamination . All sample preparation and measurement steps were performed in a laminar flow cabinet.Statistical analyses were performed using SPSS 17.0. Continuous variables are expressed as the means with standard errors. Categorical variables are expressed as percentages. The Bonferroni adjustment for multiple testing was performed using SISA 2) and accuracy tests were employed to help establish an optimal model.The gene-counting method was used to estimate the genotype frequencies of individual SNPs, which employs the standard EM algorithm for haplotype frequency estimation Our study population included 60 men with moderate to severe AGA (≥IV). A total of 17.6% of the men aged 46–55 and 27% of men over 55 displayed moderate to severe AGA. These data indicate that the prevalence of AGA in men increased with age . AdditioThe geometric mean concentrations (µg/L) of ten heavy metals in the blood samples of participants with and without AGA are shown in In the multivariate analysis, after adjusting for age and family history, the odds ratios for the body concentrations of all tested heavy metals and between the two groups (with and without moderate to severe AGA) were statistically significant (P<0.00119). In addition, the correlation coefficients between the body concentrations of all ten metals were statistically significant. Therefore, the concentrations of heavy metals were subjected to further mutual adjustment, which showed that vanadium was the sole element with an odds ratio that reached 0.001 for moderate to severe AGA (P = 0.04).The geometric mean urine concentrations (µg/L) of the heavy metals in the two groups (with and without AGA) are shown in The relationship between environmental factors, personal behaviors, dietary factors and moderate to severe AGA is illustrated in After adjusting for age and family history, the odds ratios for sleep deficiency (fewer than 6 hours per day) and scalp abnormalities were 4.47 (P = 0.04) and 2.57 (P = 0.02), respectively. In the multivariate analysis, after adjusting for age, family history and area of residence, the odds ratios for sleep deficiency and scalp abnormalities were 4.30 (P = 0.04) and 3.02 (P = 0.01), respectively.The SNP analysis was conducted in 184 individuals who were randomly selected from the original pool of 354 subjects and their age-, residence area- and smoking status-matched controls . The matched variables sufficiently increased the statistical power with an efficient sample size.Five loci  were evaluated in the SNP genotyping tests. Primers for rs11575897 were generated using “Assay by Design” based on the two 500-bp fragments flanking the SNP. Unfortunately, these primers yielded poor results due to secondary structure formation or high GC content and failed to satisfy our quality control criteria; therefore, this SNP was excluded from the study. The genotype and allele frequencies of rs1998076, rs913063, rs1160312 and rs201571 in the two groups (AGA group and the control group) were in line with Hardy-Weinberg equilibrium .The rs1998076 locus is located at position 21828045 on chromosome 20 in an intergenic region. The wild-type allele is homozygous GG, while the mutant allele is homozygous AA. The GG genotype was considered to be the control. We found odds ratios of 0.28 (P = 0.06) for the AA genotype and 0.41 (P<0.01) for the AG (heterozygous) genotype, respectively, for developing moderate to severe AGA. In the dominant model, the GG genotype was used as the control, and the combined odds ratio of the AA and AG genotypes was 0.39 (P<0.01) for developing moderate to severe AGA. In the recessive model, the GG and GA genotypes were used as the control, and the odds ratio of the AA genotype was 0.45 (P<0.01) for developing moderate to severe AGA. Compared with the G allele, the A allele had an odds ratio of 0.52 (p<0.01) for developing moderate to severe AGA.The rs913063 locus is located at position 21990418 of chromosome 20, upstream of the non-coding gene RP11-125P18.1. The wild-type genotype is CC, and the mutant genotype is AA. Using CC as the control group, we found that the AA and CA genotypes had odds ratios of 4.03 (P<0.01) and 0.72 (P = 0.37), respectively, for developing moderate to severe AGA. In the dominant model, the CC genotype was used as the control, and the combined odds ratio of the CA and AA genotypes was 1.17 (P = 0.63) for developing moderate to severe AGA. In the recessive model, the CC and CA genotypes were used as the controls, and the AA genotype was found to have an odds ratio of 4.68 (P<0.01) for developing moderate to severe AGA. Altogether, compared to the C allele, the A allele carried an odds ratio of 1.67 (P = 0.03) for developing moderate to severe AGA.The rs1160312 locus is located at position 21998503 of chromosome 20, inside the non-coding gene RP11-125P18.1. The wild-type genotype is GG, while the mutant genotype is AA. Using the GG genotype as the control, we found that the AA and AG genotypes carried odds ratios of 3.93 (P<0.01) and 0.73 (P = 0.40), respectively, for developing moderate to severe AGA. In the dominant model, the GG genotype was used as the control, and the combined odds ratio of the AA and AG genotypes was 1.21 (P = 0.55) for developing moderate to severe AGA. In the recessive model, the GG and AG genotypes were used as the controls, and AA was found to harbor an odds ratio of 4.53 (P<0.01) for developing moderate to severe AGA. Hence, compared with the G allele, the A allele had an odds ratio of 1.71 (P = 0.02) for developing moderate to severe AGA.The rs201571 locus is located at position 21961514 of chromosome 20, within an intergenic region. The wild-type genotype is CC, while the mutant genotype is TT. Using the CC genotype as the control, we found that the TT and CT genotypes harbored odds ratios of 4.24 (P<0.01) and 0.82 (P = 0.59), respectively, for developing moderate to severe AGA. In the recessive model, the CC and CT genotypes were used as the control, and TT was found to have an odds ratio of 1.87 (P<0.01) for developing moderate to severe AGA. Therefore, compared with the C allele, the T allele had an odds ratio of 1.87 (p<0.01) for developing moderate to severe AGA.2) was 0.64, the accuracy was 0.861 and the AUC was 0.926 (95% CI: 0.839–0.962). The interactions between the SNPs and the environmental or personal behavioral risk factors for AGA were not statistically significant in these models.In addition to comparing the genotypes, residence area and smoking status, other factors with significant odds ratios for the development of moderate to severe AGA were subjected to logistic regression analysis . These fThis study found that the prevalence of moderate to severe AGA in men in our study areas is 17% (60/354), higher than previously reported In 1978, vanadium was found to be an essential trace element in humans and animals et al.et al.et al. did not examine vanadium concentrations.Interestingly, there is a significant discrepancy between this study and one previously performed by Naginiene Although Su and Chen found an association between smoking and AGA Our data on environmental factors, personal behaviors and dietary intake indicated that sleep deprivation, oily scalp and the frequent consumption of soy bean drinks are correlated with moderate to severe AGA. A previous study revealed that insufficient sleep is a risk factor for sebaceous gland diseases, including seborrheic dermatitis, acne, AGA and rosacea We found that frequent soy bean drink consumption is protective against moderate to severe AGA. Soy bean drinks are rich in isoflavones, and the isoflavone metabolite equol displays high levels of antioxidant et al. showed that the risk-associated SNP rs2180439[T] is in linkage disequilibrium with rs1998076[G]. This is consistent with our findings that rs1998076[A] is a protective SNP, while rs202571[T] is a risk-associated SNP. The study by Richards et al. revealed that the r2 between rs1160312 and rs913063 is 1, indicating complete linkage disequilibrium. In other words, the information concerning rs913063 can be obtained by examining rs1160312. Although this linkage was reported previously, we performed genotyping to confirm this hypothesis. We found that both rs1160312[A] and rs913063[A] are risk-associated SNPs, corroborating the previous studies by Hillmer et al. and Richards et al.Regarding the relationship between chromosome 20 and AGA, this report is consistent with other relevant studies PAX1PAX1 is outside of the LD region, its expression pattern indicates that it affects AGA, possibly due to altering the expression of other loci in this LD region.Both rs1998076 and rs201571 are located in intergenic regions, while both rs1160312 and rs913063 are within the non-coding gene RP11-125P18.1. No transcription has been reported in any of these regions. However, previous studies have suggested that these SNPs might interact with AR gene on the X chromosome is strongly associated with male AGA SRYet al. reported that a gradual shift in the type of AGA from the earlier types (II and III) to more severe types (VI) occurs significantly with increasing age et al. reported that the prevalence of AGA Norwood III–VII was 38.52% and significantly increased with age in a study of 1124 men It has been reported that the Alopecia is a complex skin disorder observed in individuals whose conscious experience of distress is often absent and may be precipitated by environmental events, not simply the influence of inherited factors The environmental factors examined have been adequately reported, and the basis and the mechanistic explanations provided were congruent with previous findings Finally, we made an effort to adjust our independent variables in multiple logistic regression analyses. This adjustment identified several significant factors. Additional research will be required to investigate the effect of epigenetic changes on alopecia. Our epidemiological analyses are based on a sample that is representative of the Taiwanese population. Cases and controls were defined by AGA level, which was evaluated based on the Hamilton-Norwood scale by dermatological specialists at the Public Health Centers. The use of the Hamilton-Norwood scale ensured that baldness was accurately assessed according to international criteria It has been reported that genes only contribute to 13.7% of the explained variance in AGA This study identified several AGA-associated factors, including the consumption of soy bean drinks, blood concentration of vanadium, the AA genotype of rs1160312, sleep patterns and scalp status. Blood vanadium and frequent consumption of soy bean drinks may provide protective effects.File S1Supporting tables. Table S1. SNP loci reported to be associated with AGA. Table S2. AGA-associated SNP loci investigated in this study. Table S3. Genotype details.(DOCX)Click here for additional data file.


STK39as a candidate gene for blood pressure (BP) in Europeans. Subsequently, several studies have attempted to replicate the association across different ethnic populations. However, the results have been inconsistent.A recent genome-wide association study identified STK39 rs3754777 polymorphism (or proxy) and hypertension. Published literature from PubMed and Embase databases were retrieved and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model.We performed a meta-analysis to elucidate the association between the STK39 rs3754777 variant with hypertension . Further subgroup analysis by ethnicity suggested that the association was significant in Europeans  and in East Asians , but not in Africans . We further confirmed the positive association by sensitivity analysis. No publication bias was detected .Using appropriate inclusion/exclusion criteria, we identified 10 studies that included 21, 863 hypertensive cases and 24, 480 controls from different ethnicities. The meta-analysis showed a significant association of STK39 polymorphism with susceptibility to hypertension in Europeans and East Asians. Future studies should include gene–gene and gene–environment interactions to investigate the identified association.The present meta-analysis confirms the significant association of  Hypertension, whose prevalence has increased dramatically in last few years STK39) was reported as a candidate gene for BP in a GWAS on American Old Order Amish individuals STK39 gene were indicated to be associated with BP and two of the SNPs, rs3754777 and rs6749447 variants were replicated in an independent Amish sample, in four non-Amish Caucasian populations STK39 variants and hypertension Recently, several genome wide association studies (GWASs) have identified a host of BP/hypertension related loci in Europeans STK39SNP and hypertension across different ethnic populations.Therefore, in this study, we performed a meta-analysis to further clarify the association between We searched the literature databases including PubMed and Embase. The search strategy to identify all possible studies involved the use of the following key words: (“Serine/threonine kinase 39” or “STK39”) and (“blood pressure” or “high blood pressure” or “hypertension”). The reference lists of retrieved articles were hand-searched. The literature search was updated on November 21, 2012.STK39SNP with hypertension; (2) used case-control or cohort design; (3) provided sufficient data for calculation of odds ratio (OR) or relative risk (RR) with 95% confidence interval (CI), e.g., provided the genotype frequencies of the studied SNP in hypertensive cases and controls. The following information was extracted from each study: (1) name of the first author; (2) year of publication; (3) country of origin;(4) ethnicity of the study population; (5)number of subjects under hypertensive cases and controls; (6) OR or RR with 95% CI; (7) diagnostic criteria for hypertensive cases and controls; (8) covariates adjustment; (9) SNPs analyzed. Two authors independently assessed the articles for compliance with the inclusion/exclusion criteria, resolved disagreements and reached a consistent decision.The studies were included in the meta-analysis based on the following inclusion criteria: (1) evaluated the association of p>0.05). We investigated the association ofSTK39SNP with hypertension by calculating pooled OR and 95% CI. The significance of pooled OR was determined by Z test . Cochran’s Q test was performed to evaluate the heterogeneity between studies. A random- (DerSimonian-Laird method p< = 0.10) or absence (p>0.10) of heterogeneity, respectively. Similar approach was used for performing subgroup analysis by ethnicity. Sensitivity analysis by removing one study at a time was performed to evaluate the stability of the results. Publication bias was assessed by Begg’s test p<0.05 was considered statistically significant).All statistical analyses were performed using STATA version 11 .The genotypes of studied SNP was in Hardy-Weinberg equilibrium in controls of all included studies as reported by the individual studies  and rs35929607 (r2≥0.87). The number of cases in the included studies ranged from 266 to 6796. All the studies defined hypertension as SBP/DBP≥140/90 mmHg or currently on antihypertensive drugs. Since most studies provided covariates-adjusted OR (or RR) with 95%CI under an additive model but not the genotype frequencies of studied SNP in hypertensive cases and controls, we only calculated the pooled OR with 95%CI under an additive model. The characteristics of the included studies are listed in A flow chart describing the exclusion/inclusion of individual articles (or studies) has been presented as STK39 was significantly associated with hypertension . Further subgroup analysis by ethnicity showed that the association was significant in Europeans  and in East Asians , but not in Africans   .STK39 rs35929607 and hypertension was no longer statistically significant at baseline  or at follow-up . We then included the above data to re-analyze the association but the overall result did not change substantially .Sensitivity analysis confirmed the significant association between rs3754777 SNP and hypertension, with OR and 95%CI ranging from 1.09 (1.04–1.14) to 1.11 (1.06–1.17). Additionally, Fava et al. p = 0.721; Egger’s test, p = 0.744).Begg’s funnel plot was presented as STK39 variants and hypertension. The result confirms that rs3754777 SNP in STK39 is significantly associated with hypertension, and is independent of conventional environmental factors such as age, sex, body mass index (BMI) and lifestyle factors. The association was significant in Europeans and East Asians, but not in Africans. Stability of the result by sensitivity analysis and no evidence of publication bias further confirm the significant association between STK39 rs3754777 SNP and hypertension.To our knowledge, this is the first meta-analysis assessing the association between STK39 gene encodes the Ste20-related prolinealanine-rich kinase(SPAK) protein, which may regulate BP by increasing its expression and altering renal sodium excretion through its interaction with WNK kinase and cation-chloride cotransporters STK39 variants might be associated with salt sensitivity STK39 gene is involved in salt homeostasis and thereby BP regulation in humans.The STK39 SNP and sex Our study has several strengths and few limitations. First, we used the OR or RR with adjustment for confounding factors from individual study to calculate the pooled OR, which increased the accuracy of effect estimate. Second, the included studies provided data on large number of subjects and greatly improved the statistical power, which made the conclusion more convincing. Third, there was no evidence of between-study heterogeneity, suggesting the homogeneity of the study populations. However, because of inability to obtain raw data, we could perform only a study-level but not a patient-level meta-analysis, which would have enabled us to adjust for multiple risk factors. This remains one of the limitations of the study. In addition, we could not address the effect of gene–gene/gene–environment interactions in this meta-analysis, though several papers have reported the effect of interaction between STK39 variants and hypertension in Europeans and East Asians but not in the Africans. Large-scale prospective studies with consideration of gene-gene/environment interactions are required to further dissect the causal nature of identified association.In conclusion, the present meta-analysis confirmed the significant association between


TGFB1 gene have been studied in relation to coronary heart disease (CHD) risk, but the results were inconsistent.Genetic variations in TGFB1 genetic variation in CHD risk. Articles that reported the association of TGFB1 genetic variants with CHD as primary outcome were searched via Medline and HuGE Navigator through July 2011. The reference lists from included articles were also reviewed.We performed a systematic review of published studies on the potential role of Data were available from 4 studies involving 1777 cases and 7172 controls for rs1800468, 7 studies involving 5935 cases and 10677 controls for rs1800469, 7 studies involving 6634 cases and 9620 controls for rs1982073, 5 studies involving 5452 cases and 9999 controls for rs1800471, and 4 studies involving 5143 cases and 4229 controls for rs1800472. The pooled odds ratios (ORs) for CHD among minor T allele carriers of rs1800469, minor C allele carriers of rs1982073, and minor C allele carriers of rs1800471 versus homozygous major allele carriers was 1.14 , 1.18 (95% CI: 1.04-1.35), and 1.16 (95% CI: 1.02-1.32), respectively. No substantial heterogeneity for ORs was detected among the included Caucasian populations for all SNPs. However, for rs1800471, the statistical significance disappeared after adjusting for potential publication bias. No significant association was found between rs1800468 and rs1800472 variants and CHD risk.TGFB1 have a 15% increased risk of CHD.Minor allele carriers of two genetic variants (rs1800469 and rs1982073) in  Transforming growth factor-β1 (TGFβ1) is a ubiquitously expressed multifunctional cytokine that is involved in many physiological and pathological processes. TGFβ1 has been demonstrated to be of fundamental importance in the development, physiology and pathology of the vascular system. Research into the mechanisms of TGFβ1 signaling over the past two decades has led to the development of a well-accepted canonical signaling cascade involving heterotetrameric complexes of type I and type II serine/threonine-kinase transmembrane receptors together with Smad transcription factors that act as intracellular signaling effectors. However, the exact mechanisms by which TGFβ1 signaling exerts its effects within the vasculature are still incompletely understood. AccordiTGFB1 genetic variations that could cause variable constitutive or induced expression of TGFB1 or protein structural changes and, as a result, changed TGFβ1 activity, have been identified. They include rs1800468 (−800 G/A) and rs1800469 (−509 C/T) in the promoter region, rs1982073  and rs1800471  in the signal peptide region, and rs1800472  in the region encoding the precursor part of the protein[TGFB1 gene in Caucasian populations[TGFB1 genetic variants in relation to CHD risk exists; therefore, we performed a meta-analysis of published data that tested for TGFB1 genetic variants associated with CHD risk.Although the amino acid sequence of the active form of TGFβ1 is highly conserved across mammalian species,14,15, culations,17. The ulations,20, but ulations,22, and ulations. This maulations,25. It hTGFB1 gene polymorphisms and primary outcomes of CHD, coronary artery disease or myocardial infarction (MI), 3) used validated coronary heart disease phenotypes , and 4) involved unrelated participants.For inclusion, studies 1) had to be case–control or cohort in design, 2) examined the association between TGFB1 gene polymorphism and CHD risk published before July 2011 were identified by comprehensive electronic searches of Medline and HuGENet. Terms used for the searches were “TGFB1,” “ischemic heart disease,” “coronary heart disease,” “coronary artery disease,” “acute coronary syndrome,” “myocardial infarction,” and “angina pectoris” combined with “gene,” “genetic,” “variant,” “mutation” or “polymorphism.” Hand searches for related articles among the reference lists of included articles were also performed. If essential information of a study was not presented in the publication, authors were contacted for details. The study was excluded if the information could not be obtained. In addition, the relevant data from the two latest large-scale meta-analyses of CHD GWA studies  were included in the analyses.The first author, published year, country, study population, mean age of participants, gender distribution, study design, sample size, outcome, diagnostic criteria, genotyping method, characteristics of the controls, allele frequencies, and genotype distributions were extracted. In PROCARDIS and CARDDeviance from Hardy-Weinberg equilibrium (HWE) was assessed for the controls of each study using Fisher’s exact test. For an Iranian study, only daFifteen citations were identified through the original literature search; none were meta-analyses-23,31-37None of the genetic variants were associated with CHD risk when applying a recessive model (data not shown). Rs1800468 and rs1800472 were not associated with CHD in either co-dominant or dominant model . The TT genotype conferred a non-significant risk of similar magnitude . The CC genotype conferred a 1.25 times increased risk, but this was not statistically significant .To evaluate the influence of the individual studies on the pooled ORs for rs1800469, rs1982073 and rs1800471, each time, a single study involved in the meta-analysis was deleted. The Rotterdam study and the TGFB1 gene including rs1800468, rs1800469, rs1982073, rs1800471 and rs1800472 might be associated with CHD risk, but data have yielded conflicting results. Possible concerns in genetic association studies are that a positive association might be spurious, while a negative result might be due to a small sample size. In this meta-analysis, we incorporated all eligible studies to date and provided some evidence that rs1800469 and rs1982073 in the TGFB1 gene are associated with CHD risk in Caucasian populations. The inconsistency between the previously reported results for these SNPs might be due to the small sample sizes in most of the studies, especially in combination with a modest effect.Several studies have been carried out to test the hypothesis that genetic polymorphisms in the in vivo and in vitro recruitment of transcription regulator AP1 to -509 C  leading to transcriptional repression of the TGFB1 gene. However, the exact functional variant in this gene region merits further identification. In support of the aforementioned positive association between CHD risk alleles of TGFB1 and increased TGFβ1 production, increased TGFβ1 levels were observed in different stages of plaque development in some histological studies[SMAD3 gene that encodes one of the downstream activating transcriptional mediators (Smad3) of TGFβ1 signalling[Circulating TGFβ1 levels are predominantly under genetic control with a heritability of 0.54. Both th studies,38-40. I studies-5,7,8,12 studies. Recentl studies-44. A gegnalling.h2 = 0.52) of such abnormal enlargement of the coronary artery in the pathogenesis of coronary artery disease was observed, especially in the proximal coronary artery[TGFBR1, TGFBR2[SMAD3[It has previously been shown that abnormal enlargement of human coronary arteries  occurs in response to the development of intimal plaque-49, whicy artery. Interesy artery-56 and iy artery,58. Recey artery,59. Furty artery, whereas1, TGFBR2,62, and BR2[SMAD3) or TGFβBR2[SMAD3 are implP values for Q-tests were > 0.05. Second, the results in the co-dominant model for rs1800469 and rs1982073 were dominated by the Rotterdam[Some limitations of this meta-analysis should be acknowledged. First, a relatively small number of studies for each SNP was included, and therefore we cannot rule out heterogeneity completely in Caucasian populations although most of the otterdam and the otterdam as shownTGFB1 gene and CHD risk in Caucasian populations. Enhanced TGFβ1 signalling may therefore be involved in the pathogenesis of CHD.In conclusion, the present study demonstrates an association between rs1800469 and rs1982073 in the CHD: Coronary heart disease; CI: Confidence interval; GWA: Genome-wide association; HWE: Hardy-Weinberg equilibrium; LD: Linkage disequilibrium; ORs: Odds ratios; VSMC: Vascular smooth muscle cells.The authors declare that they have no competing interests.YL, JMB, RMB, OF, AG, CARDIoGRAM Consortium, MM, and EJF have made substantial contributions to conception and design, or acquisition of the data, or analysis and interpretation of data; YL, JMB, RMB, OF, and EJF have been involved in drafting the manuscript or revising it critically for important intellectual content; and all authors have given final approval of the version to be published. All authors read and approved the final manuscript.Members and affiliations of the CARDIoGRAM Consortium are listed in the Additional files.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/13/39/prepubAdditional acknowledgments for the PROCARDIS study and the CARDIoGRAM study.Click here for fileTable S1. Summary of the meta-analysis of studies examining the association between TGFB1 polymorphisms and coronary heart disease risk. Click here for fileTable S2. Results from the leave-1-out sensitivity analysis. Click here for fileFigure S1. Funnel plots with pseudo 95% confidence intervals for rs1800469 analysed according to different genotype contrasts. A. Comparison of the homozygous TT genotype with the wild type CC genotype ; B. Comparison of the heterozygous CT genotype with the wild type CC genotype ; C. Comparison of the TT+CT genotype with the wild type CC genotype . Figure S2. Funnel plots with pseudo 95% confidence intervals for rs1982073 analysed according to different genotype contrasts. A. Comparison of the homozygous CC genotype with the wild type TT genotype ; B. Comparison of the heterozygous TC genotype with the wild type TT genotype ; C. Comparison of the variant genotype of CC+TC with the wild type TT genotype . Figure S3. Funnel plots with pseudo 95% confidence intervals for rs1800471 analysed according to different genotype contrasts. A. Comparison of the homozygous CC genotype with the wild type GG genotype ; B. Comparison of the heterozygous GC genotype with the wild type GG genotype ; C. Comparison of the variant genotype of CC+GC with the wild type GG genotype . Click here for file


Tumor necrosis factor-α (TNF-α) 308 G/A gene polymorphism has been reported to be associated with susceptibility to silicosis. However, the relevant study results are still inconsistent.A meta-analysis was performed in order to drive a more precise estimation of the relationship between TNF-α-308 G/A gene polymorphism and susceptibility to silicosis. Electronic databases were searched and nine separate studies were included. The pooled odds ratios (ORs) and the corresponding 95% confidence internal (CI) were calculated by a fixed effect model.OR=1.45, 95%CI: 1.20-1.760, P=1.58E4; for GA vs. GG: OR=1.53, 95%CI=1.25-1.86, P=3.11E5; for A allele vs. G allele: OR=1.27, 95%CI=1.08-1.50, P= 0.004). In the subgroup analysis, significantly increased silicosis risk was also found among Asians , for GA vs. GG: OR=1.71, 95%CI=1.33-2.20, P=3.44E5), for A allele vs. G allele: OR=1.45, 95%CI=1.17-1.80, P=0.001). However, no significantly increased risk was found among non-Asians for all genetic models.A total of 1267 cases and 1214 controls were included. In the overall analysis, significantly increased silicosis risk was found (for GA+AA vs. GG TNF-α-308 G/A polymorphism might lead to an increased risk of silicosis susceptibility, especially for Asians. However, further studies with large sample sizes should be conducted to confirm the association. Silicosis is one of the most important occupational diseases worldwide , which iTNF-α is an important mediator of inflammatory response, and is involved in the pathogenesis of various human autoimmune and inflammatory diseases ,19. TNF-In the current study, a meta-analysis of nine individual studies was conducted to determine whether there was a relationship between TNF-α-308G/A polymorphism and silicosis risks in the whole population.PubMed, Web of Science, Embase, China National Knowledge Infrastructure for relevant studies published in English or Chinese(CNKI), WanFang, Database of Chinese Scientific and Technical Periodicals (VIP) were systematically searched using the following search terms: “tumor necrosis factor-α” or “tumor necrosis factor-alpha” or “TNF-α” or “TNF-alpha” and “silicosis” combined with “polymorphism” or “mutation” or “variant ” and the last search was updated to April 25, 2013. Animal studies or non-English and Chinese language articles were not included. All objects included studies were approved by the Medical Ethics Committee.The inclusion criteria are: 1) information on the evaluation of TNF-α gene-308G/A polymorphism and the susceptibility to silicosis; 2) sufficient published data for estimating the odds ratio (OR) with 95% confidence interval (CI); 3) studies using a case-control design; 4) not republished data; 5) not animal studies.Information was extracted from all selected publications by two investigators separately. If these two investigators could not reach a consensus; disagreements were discussed and resolved by a third investigator. For each of the included articles, information including first author, year of publication, source of controls, study population (ethnicity), total numbers of patients and controls, and frequencies of TNF-α gene-308G/A polymorphism in patients and controls was extracted.Q statistic and the I2statistic. P <0.10 in Q-test indicated no heterogeneity among studies. P<0.1 rather than 0.05 was considered significant heterogeneity for the χ2-based Q testing and a value of 0% for I2 indicated no heterogeneity and increasing percentage implied increased heterogeneity. That is, I2 will be used to estimate total variation across studies that are due to heterogeneity rather than chance  [OR was analyzed using Z test, and P < 0.05 was considered as statistically significant. Sensitivity analysis was performed by sequentially excluding individual studies to assess the stability of the results [2 test in the controls [P<0.05 was considered representative of statistically significant publication bias). Statistical analysis was performed with Stata11.0 , and all P-values were two-tailed. Power analysis was performed by Power Analysis (PASS) 2008(http://www.ncss.com/pass.html)The association between TNF-α-308 G/A polymorphism and the risk of silicosis was estimated by calculating a pooled OR and 95%CI under a dominant model (GA+AA vs. GG), a recessive model (AA vs. GA+GG), additive model (AA vs. GG) and an allele model (A vs. G). The fixed-effects model or random-effects model was used depending on whether or not heterogeneity existed among studies. A subgroup analysis was carried out with respect to ethnicity. Heterogeneity among studies was examined with Cochran’s geneity) ,37. The  results . Hardy-Wcontrols . The potcontrols . Funnel The flow diagram of the search process is exhibited in The initial search of databases identified 410 potentially relevant articles, of which 401 articles  were rejected because of their obvious irrelevance to the purpose of this study. In addition, 9 reviews, 3 meeting abstracts and 26 republished studies were excluded. Finally, a total of nine published articles including 1267 cases and 1214 controls reported the relationship between TNF-α-308G/A gene polymorphism and the susceptibility to silicosis. The countries of these studies include China, USA, and South Africa. Seven studies involving Asians include 852 patients and 940 controls, and the two studies involving non-Asians include 415 patients and 274 controls. The total nine studies provide the numbers of allele A and allele G in both silicosis patients and controls. The Hardy–Weinberg equilibrium had been tested for all polymorphisms in the control groups. I2=0.0%, P for heterogeneity =0.753; GA vs. GG: I2=18.5%, P=0.278), the dominant model , the recessive model , and the allele model . Therefore, a fixed-effects model was used for all the genetic models. In overall analysis, significantly increased silicosis risk was found for GA+AA vs. GG , for GA vs. GG , and for A allele vs. G allele , but, not significantly increased risk was found amongnon-Asians for all genetic models . Thereby, the current study indicates TNF-α-308G allele might increase silicosis risk.The current meta-analysis suggests a significant relationship between TNF-α-308G/A gene polymorphism and silicosis risk under the dominant genetic model for 1.45(95%CI: 1.20-1.760), but no significant association is found under the recessive genetic model  seem to have no significant association with the silicosis risk in the total population. These findings show that TNF-α-308G/A polymorphism might help to explain the individual differences in the susceptibility to silicosis. Considering the effect of genetic background on the results, we also performed subgroup analysis with respect to ethnicity. Because of few studies on non-Asians, the subgroup analysis was carried out for Asians. The results show that the Chinese people with the genotype GA/AA vs. GG may be more susceptible to silicosis. We found no significant association for AA versus GG model and AA versus GA/GG model, which might be attributed to the low statistical power due to the low AA genotype frequency. Meanwhile, no significance was found in non-Asians for the genotype GA/AA vs. GG; the possible reasons of such a result may be the differences in the genetic backgrounds and living environments. In addition, only two included studies were non-Asians, which made the stratified analysis not so reliable. Therefore the result should be interpreted with caution, and additional studies with further large-scale case-control ones are needed to validate the result. However, according to the power analysis, our study had greater than 80% to detect the effects of TNF-α polymorphism on silicosis, assuming an OR of 1.45. This meta-analysis at least provides new clues to the ethnic differences.The present meta-analysis of nine studies provides more comprehensive analysis on the relationship between TNF-α-308A/G gene polymorphism and susceptibility to silicosis. The genotype Q variants of model effects, particularly when they have a severe effect in a recessive model. Finally, our result was based on unadjusted estimates; therefore, more precise analysis should be performed if individual data were attainable, which would allow for the adjustment by other factors, including age, family history and environmental factors.The overall comparisons did not show heterogeneity or publication bias, indicating that the results were statistically robust. However, some limitations from the following aspects should be addressed. First, a disease is largely affected by the interaction between genotypes and environment. People from different places have specific work environments, and genetic characteristics may be different among races, which should be considered in the study. Moreover, silicosis usually has a long developing stage that can be affected by a number of factors such as age, sex, working tenure, and many of them were not included in this study because of the lack of original data, which cause some bias. Second, larger sample sizes are necessary in future studies to eliminate the interference factors of genetic risk contributed by the -308G/A polymorphism might lead to an increased risk of silicosis susceptibility, especially for Asians. However, in order to better to estimate the association of other variables with the susceptibility to silicosis, it is necessary to carry out further researches with a larger number of worldwide studies in standardized and unbiased ways.Despite those limitations, this systematic review of the association of TNF-α-308G/A gene polymorphism with silicosis risk is statistically more convincing than any single study. This meta-analysis based on a large sample size strongly gives a strong conclusion that the Checklist S1Prisma checklist.(DOC)Click here for additional data file.