Focal adhesion (FA) family genes have been studied as candidate genes for osteoporosis, but the results of genetic association studies (GASs) are controversial. To clarify these data, a systematic assessment of GASs for FA genes in osteoporosis was conducted.We developed Cumulative Meta-Analysis of GAS-OSTEOporosis (CUMAGAS-OSTEOporosis), a web-based information system that allows the retrieval, analysis and meta-analysis  of data from GASs on osteoporosis with the capability of update. GASs were identified by searching the PubMed and HuGE PubLit databases.1 (COL1A1) G2046T , COL1A1 G-1997T  and integrin β-chain β3 (ITGB3) T176C (recessive and additive models). In COL1A1 G2046T, subgroup analysis has shown significant associations for Caucasians, adults, females, males and postmenopausal women. A differential magnitude of effect in large versus small studies  was detected for the variant COL1A1 G2046T.Data from 72 studies involving 13 variants of 6 genes were analyzed and catalogued in CUMAGAS-OSTEOporosis. Twenty-two studies produced significant associations with osteoporosis risk under any genetic model. All studies were underpowered (<50%). In four studies, the controls deviated from the Hardy-Weinberg equilibrium. Eight variants were chosen for meta-analysis, and significance was shown for the variants collagen, type I, αThere is evidence of an implication of FA family genes in osteoporosis. CUMAGAS-OSTEOporosis could be a useful tool for current genomic epidemiology research in the field of osteoporosis. Osteoporosis is a common skeletal disease characterized by generalized reduction in bone mineral density and microarchitectural deterioration of bone tissue, leading to impaired skeletal strength and increased susceptibility to fracture . Genetic1 (COL1A1) gene, especially its variant G2046T. Other genes studied in the FA family include the genes insulin-like growth factor I (IGF-I), integrin β-chain β3 (ITGB3), α-actinin-3 (ACTN3), COL1A2 and type 1 insulin-like growth factor receptor (IGF-IR). However, the results of the GASs involving genes of the FA pathway and osteoporosis are controversial and inconclusive, possibly because of methodological limitations, including inadequate sample size, patient selection, ethnicity of the populations studied and lack of adjustments for confounders . CUMcumagas@med.uth.gr).CUMAGAS-OSTEOporosis is a dynamic system, since it has the capacity of continuous updating. Authors of published and unpublished studies may contribute their data by entering their studies' data into a prespecified data entry form (CUMAGAS-FORM) . FurtherACP1, ACTN3, ADRB1, AKT1, COL1A1, COL1A2, COMP, CREBBP, CSNK1D, CTNNA3, CTNNB1, DRD2, FGFR1, GRB2, GRB2, IGF-I, IGF-IR, ITGA1, ITGA2, ITGA2B, ITGB3, KDR, PARD6A, PDGFRA, PDGFRB, PIK3CA, PRKACB, PTPN1, SMAD2, SMAD3, SMAD4, SPP1, TCF7, TGFBR1, TGFBR2, VEGFA, VWF, osteoporosis, gene, polymorphism, allele and variant. The bibliographies in the articles that these searches identified were used to find further references. The HuGE PubLit database [All studies published before June 2010 were identified by conducting extended computer-based searches of the PubMed and HuGE PubLit databases. The search criteria in the PubMed database included a combination of the following terms: Focal adhesion, database  was searThe eligible studies fulfilled the following inclusion criteria: (1) inclusion of cases with clinically diagnosed osteoporosis and controls free of osteoporosis, (2) information provided on genotype frequency or risk estimates , (3) use of DNA-based analytical methods for genotyping and (4) studies of humans. Studies investigating disease progression, severity, phenotype modification, response to treatment or survival were excluded from our study. Case reports, editorials, review articles and non-English-language articles were also excluded. Finally, family-based studies were excluded because of different design settings. Abstracts of retrieved studies were independently read by two investigators (CD and EZ) to assess their appropriateness for this study. Full-text articles of the studies were evaluated (by CD and EZ) according to the inclusion criteria. The results were compared, and disagreements were resolved by consensus.Published GWASs of osteoporosis cited in the HuGE PubLit database  and the From each article, the following information was extracted: first author, year of publication, ethnicity of the study population, study design, demographics and number of cases and controls for each genotype and effect size. The frequencies of the alleles and the genotypic distributions were extracted or calculated for both the cases and the controls. The reference single nucleotide polymorphism identification numbers (rs numbers), the chromosomal gene position and the nucleotide base changes for all genetic variants were identified by performing extended searches of bioinformatics databases ,14-16.I2 metric [PQ < 0.10 . The pooled OR was estimated using the random effects (RE) model [[et al. [P-value for Harbord's test was PH<0.05. The meta-analysis consisted of the main  analysis, which included all available data, as well as subgroup analyses by ethnicity, gender, age, menopausal status and sensitivity analysis which examined the effect of excluding specific studies [Prior to meta-analysis, the risk effect of gene variants for the allele contrast and the dominant models were evaluated separately for each study. All associations were indicated as odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs). In the meta-analysis, the heterogeneity between studies was tested using the Q-statistic ,18, and ) model [; see als) model . The RE[[et al. . This ef studies .The distribution of each variant in the control group was tested for the Hardy-Weinberg equilibrium (HWE) . HWE indThe literature review identified 169 titles in the PubMed and HuGELit databases that met the search criteria. The search in HuGE PubLit and the databases for GWASs traced articles already identified by PubMed. After abstract selection, 132 articles remained. When an article provided data for different populations, then each population was considered as a different study -27. ThirThe characteristics of each study and the association results of variants are shown in Additional file Studies were conducted in various populations of different racial descent: Sixty-six studies involved solely Caucasians, two studies recruited East Asians, three studies involved Turks and one study involved a population of Mexican origin. Twenty-three studies involved only postmenopausal women. Twelve studies provided data for men and women. One study involved children.COL1A1 G2046T, COL1A1 RsaI intron 5, COL1A2 PvuII and ITGB3 T176C.The distribution of genotypes in the control group deviated from HWE in 4 studies, and in 20 studies the HWE deviation could not be tested. In all studies, the statistical power for detecting a significant risk effect was lower than 50%. In total, 22 studies produced significant associations with osteoporosis risk under any genetic model. The significant associations concerned the variants COL1A1 G2046T , COL1A1 G-1997T (rs1107946), COL1A1 -1663T ins/del (rs2412298), COL1A1 MspI 26 kb upstream, COL1A1 RsaI intron 5, COL1A1 MnII exon 52, IGF-I 192 bp CA and ITGB3 T176C (rs5920). Table COL1A1 G2046T, COL1A1 G-1997T and ITGB3 T176C. Additional file COL1A1 G2046T.In total, eight variants were investigated in two or more studies, and their results were meta-analyzed: COL1A1 G2046T  with the heterogeneity between studies being significant . In subgroup analysis, a significant association was shown for Caucasians , adults , females , males  and postmenopausal women . The recessive, dominant, additive and codominant models produced similar results . The sensitivity analysis for HWE did not alter the pattern of results.In particular, there was a significant overall association for the allele contrast of the variant COL1A1 G-1997T  and ITGB3 T176C (recessive and additive models). However, these results were based on a small number of studies, and therefore safe conclusions could not be drawn. In the overall meta-analyses for the allele contrast, a differential magnitude of effect in large versus small studies was detected only for the variant COL1A1 G2046T (PH = 0.01).Significant results were also shown for the variants COL1A1 G2046T, COL1A1 G-1997T and ITGB3 T176C. Type I collagen is the major protein constituent of bone and is therefore a strong and plausible candidate gene for osteoporosis. The COL1A1 G2046T polymorphism is a single base pair substitution (G → T) within the regulatory region of the COL1A1 gene [COL1A1 G-1997T polymorphism has been identified in the proximal promoter of COL1A1 at position -1997 and is in linkage disequilibrium with the COL1A1 G2046T polymorphism [COL1A1 in the bones and the fact that these variants seem to play a major role in the function of the gene, the significant association found in our results may encourage intensive research in this area. The ITGB3 T176C polymorphism changes the conformational structure of the β3-subunit of integrin [3-subunit is known to play a key role in the resorptive function of osteoclasts, as shown in vitro and in transgenic animal studies [3 may influence bone remodeling and subsequent bone loss and risk of osteoporotic fractures.In this project, the currently available data from GASs on human FA family genes in osteoporosis were catalogued. Then the data were synthesized, and the involvement of FA gene variants in disease susceptibility was assessed comprehensively. The eligible GASs were catalogued in a publicly available web-based database and information system called CUMAGAS-OSTEOporosis . In tota1A1 gene . The COLmorphism . There imorphism , but it integrin . The int studies . GeneticCUMAGAS-OSTEOporosis is an evidence-based information system for systematically searching, reviewing and synthesizing data for GASs of osteoporosis, with the capacity for continuous updating. CUMAGAS is being expanded to additional complex diseases such chronic lymphocytic leukemia, peripheral arterial disease, hypertension and osteoarthritis ,9,35,36.The GWASs of osteoporosis have not highlighted a significant role for the FA family of genes. However, the commercial genotyping platforms  may undeMost of the published GASs are underpowered for detecting the minor contribution of common alleles. For example, a sample size of more than 10,000 patients is needed to achieve >80% power to detect a significant OR between 1.1 and 1.5 (modest effect) for a polymorphic locus in association with a complex disease . Meta-anTwo problems in human genome epidemiology research are that negative studies are frequently unpublished and some studies do not provide extractable data, which lead to the well-known phenomenon of publication bias . Howeveret al. [Publication bias was tested using the method proposed by Harbord et al. , which iet al. , and it et al. ,47. Howeet al. ,48.a priori biological justification for their choice. Consequently, the interpretation of the results can be problematic, especially when all genetic contrasts are significant as in the case of COL1A1 G2046T. In these cases, the introduction of the recently proposed generalized OR (ORG) as an overall genetic risk effect may be a remedy [G is a single statistic that summarizes the magnitude and significance of the association without considering the hash of possible contrasts, and thus the interpretation of the results is straightforward [G metric and the continuous phenotype of osteoporosis .The significance of risk effects in the GASs was assessed using the OR metric for various genetic models  by merging genotypes. These models are not independent, and there is no a remedy . The ORGtforward . The metIn the meta-analysis, various genetic contrasts in different populations were explored, since there is no biological justification for choosing a specific contrast . Thus, aThe phenotypic heterogeneity of osteoporosis in the included studies in our synopsis makes the effort to combine the findings of GASs meaningfully in the complex field of osteoporosis a difficult task. Thus, in the presence of the large heterogeneity, the results should be interpreted with caution. There may be fundamental differences in the nature of genetic susceptibility to osteoporosis between postmenopausal and premenopausal women and between the two sexes or even among patients of different ethnicities. Furthermore, environmental factors, particularly nutrients, have to be accurately evaluated together with complex genotyping, to weigh their importance in revealing functional variants with respect to specific genetic background ,56. Our There is evidence implicating the activity of the FA family of genes in osteoporosis. Future studies designed to investigate epistatic and gene-environment interactions may help in deriving more conclusive claims about the role of these genes in osteoporosis. The CUMAGAS-OSTEOporosis information system can be a useful resource for reviewing and interpreting the findings of the accumulating genomic epidemiologic research in osteoporosis.The authors declare that they have no competing interests.TK conceived the study. EZ and TK were the principal investigators. EZ, CD and TK retrieved and assessed the articles. EZ, AK and TM developed the algorithms and the information system. EZ and PR performed the analysis. EZ, CD and TK drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/9/9/prepubSupplementary Table 1Click here for fileSupplementary Table 2Click here for fileSupplementary Figure 1Click here for file


GSTM1) gene polymorphism and laryngeal cancer risk have reported conflicting results. The aim of the present study was to conduct a meta-analysis assessing the possible associations of GSTM1 gene polymorphism with laryngeal cancer risk.Studies investigating the association between glutathione S-transferase M1 . When stratifying for race, GSTM1 null genotype exhibited increased laryngeal cancer risk in Caucasians , while no significant association was detected in Asians . In the subgroup analysis based on source of controls, significant associations were observed in the population-based studies  yet not in the hospital-based studies . Furthermore, in the subgroup analysis based on sample size, significant associations were also found in studies with at least 50 cases and 50 controls  but not in studies with fewer than 50 cases or 50 controls .Seventeen studies were included in the present meta-analysis . The combined results based on all studies showed that GSTM1 gene polymorphism was associated with laryngeal cancer, particularly in Caucasians, and these associations varied in different subgroup, which indicated that population-based study with larger sample size was more appropriate in design of future study.This meta-analysis supported that the  Squamous cell carcinoma (SCC) of larynx is the most frequent malignancy in the head and neck region, the risk of which results from complex interactions between many genetic and environmental factors GSTs), which can be divided into classes of alpha, mu, pi, sigma and theta on the basis of chromosomal location and sequence homology, are a family of cytosolic enzymes that play an important role in the detoxification of potential carcinogens GSTs gene family, GSTM1 gene located on the chromosome 1p13.3, participates in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons present in tobacco GSTM1 genotypes has been investigated in relation to various types of cancers Human glutathione S-transferases  guidelines GSTM1 polymorphism and laryngeal cancer risk were included. The following inclusion criteria were used for the paper selection: 1) The association of laryngeal cancer with GSTM1 polymorphisms was clearly evaluated; 2) Only the case-control studies were considered; 3) The paper described the diagnoses of laryngeal cancer and the sources of cases and controls; 4) The polymorphism was determined by polymerase chain reaction (PCR)-based method, using the peripheral blood sample; 5) Enough information about the number of laryngeal cancer cases and controls studied with the different GSTM1 genotypes were offered. Accordingly, the following exclusion criteria were also used: 1) Study design other than case-control method; 2) Not offering the source of cases and controls and other essential information; 3) Reviews and repeated literature were also excluded.All papers involving studies that investigated From each of the eligible papers, the following data were extracted: first author’s surname, publication year, country of origin, ethnicity, source of controls, genotyping methods, and numbers of different genotypes of cases and controls, respectively. Data were extracted independently by the same authors previously mentioned, and consensuses were reached on all items. Discrepancies were resolved by discussion.GSTM1 polymorphism was estimated by odds ratio (OR) and 95% confidence interval (CI), based on the genotype frequencies in cases and controls. To calculate the pooled OR, the fixed-effect model and the random-effect model were used. The significance of the pooled OR was determined by the Z-test and P<0.05 was considered as statistically significant. Heterogeneity was tested by the 2I statistic P<0.05 was considered representative of statistically significant publication bias). Sensitivity analysis was conducted by removing each individual study in turn from the total and re-analyzing the remainder. Statistical analysis was done using the program Review Manager 5.1.2  and the statistical software Stata10.1 .The strength of the associations between laryngeal cancer and the GSTM1 status of laryngeal cancer The literature search identified 90 related articles through PubMed, Embase, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure. With the step of screening the title or abstract, 24 eligible studies were selected . Of the 2I = 0). Moderate heterogeneity was detected in the analysis of Caucasian population (2I = 43%), population-based study (2I = 50%), the studies stratified by sample size  and the overall studies (2I = 44%). High heterogeneity was found in the analysis of Asian population (2I = 58%). A random-effect model was used in the analysis of Asian population, and fixed-effect models were selected in other analyses.No heterogeneity was observed in the analysis of hospital-based study , indicating that our results were statistically robust. In order to compare the difference and evaluate the sensitivity of the meta-analyses, we also reported the results of the random effects model, the combined OR was 1.21 (95% CI = 1.03∼1.44), similar to the results of the fixed effects model.P = 0.11) or subgroup analyses. Egger’s test also suggested the absence of publication bias in either overall analysis (P = 0.06) or subgroup analyses.Funnel plots were created to assess the possible publication biases, the shape of which did not reveal any evidence of obvious asymmetry . Begg’s GSTM1 gene polymorphism may contribute to risk of laryngeal SCC. However, the results of these studies assessing the association between laryngeal SCC susceptibility and GSTM1 genotype have been contradictory. Hence, we undertook this meta-analysis, which supported that GSTM1 gene polymorphism was associated with laryngeal cancer and suggested that GSTM1 null genotype had an effect on the risk of developing laryngeal cancer among Caucasians.A series of studies have indicated that GSTM1 was known to abolish enzyme activities and therefore has been linked with an increase in a number of cancers, most likely due to increased susceptibilities to environmental toxins and carcinogens. Previous meta-analyses suggest that GSTM1 null genotypes might have a correlation with increased susceptibilities to breast cancer GSTM1 gene polymorphism with hepatocellular carcinoma GSTM1 gene polymorphism and laryngeal SCC susceptibility. The combined results based on all studies showed that GSTM1 null genotype was associated with increased laryngeal cancer risk . Considering the variation of ethnic populations, we further utilized subgroup analysis with respect to ethnicity. When stratifying for race, GSTM1 null genotype exhibited increased laryngeal cancer risk in Caucasian populations , lack of significant association was detected in Asian populations , suggesting a possible role of ethnic differences in genetic backgrounds and the environment they live in. On the other hand, it is likely that the observed ethnic differences may be due to chance because small number of studies among Asians may lead to insufficient statistical power to detect a slight effect.As one of the most important phase II enzymes, GSTM1 null genotype was associated with laryngeal cancer risk in the population-based studies, which supported the association between GSTM1 polymorphism and laryngeal cancer risk. However, in the hospital-based studies, no significant association was detected. Since it is conceivable that such controls may just represent a sample of ill-defined reference population, and may not be representative of the general population very well, particularly when the genotypes under investigation were associated with the disease conditions that the hospital-based controls may have. In the subgroup analysis by sample size, the pooled OR in studies with larger sample size (number of cases and controls ≥50) was approximately the same in all the studies, which indicated that larger sample size with adequate power was one of the important factors in the design of case-control studies. The use of population-based studies with larger sample size is, therefore, more appropriate in such genetic association studies. It was worth mentioning that power was an issue as limited numbers were in the Asian, small study, and hospital-based groups, therefore, the case-control data were not enough to strongly support our meta-analysis result in these subgroups, which must be interpreted with caution.The subgroup analysis based on source of controls also suggested that the Several limitations of this study should be addressed. First, the sample size was still relatively small for some stratified analyses. Second, only published studies were included in the meta-analysis, therefore, publication bias may have occurred, even though the use of a statistical test did not show it. Third, we were unable to obtain information from most studies on the presence or absence of a history of smoking, because of lack of the investigation of gene-environment interactions. Finally, our meta-analysis was based on unadjusted estimates, whereas a more precise analysis could be performed if individual data were available and would allow for an adjustment estimate. Despite the limitation, our meta-analysis significantly increased the statistical power of the analysis based on substantial number of cases and controls from different studies.GSTM1 gene polymorphism was associated with laryngeal cancer, particularly in Caucasians. As studies among other ethnic populations are currently limited, it is of great essentiality to conduct large-sample studies with wider spectrum of subjects to investigate the relationship between GSTM1 gene polymorphism and laryngeal SCC risk, which would greatly help summarize the results from published papers.In conclusion, this meta-analysis supported that the Checklist S1(DOC)Click here for additional data file.


HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case–control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk , while rs112587690 P1P3 frequency resulted significantly higher in the control group . These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690. Cutaneous malignant melanoma is the most aggressive common skin tumor. It is characterized by a multifactorial etiology. Sun exposure and genetic susceptibility have been proposed as major etiological and predisposing factors –3.RAS proto-oncogenes, known as HRAS, KRAS, and NRAS, which encode small GTP-binding proteins. RAS genes have been characterized as major participants in the development and progression of a series of human tumors, such as gastrointestinal cancer, lung cancer, thyroid cancer, melanoma, and breast cancer. It was reported that just one point mutation occurring in codons 12, 13, or 61 and rarely in cod0on 146 could result in continuous stimulation of cell proliferation; thus, codons 12, 13, 61, and 146 are also called mutation hotspots. Alternatively, a 5- to 50-fold amplification of the wild-type gene results in over-expression and constitutive hyper-activation of the gene [HRAS protein independently of external signals [Mammalian cells contain three functional  signals .HRAS sequence were described [HRAS cDNA position 81T > C (rs12628), originally described by Taparowsky et al. [HRAS, which is located in a wobble base position. Recently, it was demonstrated that the C-allele of this SNP could increase the risk of oral carcinoma, colon, and gastric cancer [HRAS rs12628 polymorphism and to understand its role fully.Besides the mutation hotspots, inherited polymorphisms in the escribed , 10. A sy et al. , was sho1T > C rs628, origc cancer . rs12628c cancer . HoweverWhile sequencing 15 melanoma cell lines for genes belonging to the MAPK pathway , we founHere, we tested the association of rs12628 and rs112587690 with the risk of cutaneous melanoma.Germ line DNA was isolated from blood of 118 Caucasian healthy donors and 141 Caucasian melanoma patients with metastatic melanoma that underwent immunotherapy with high-dose IL-2 at the Surgery Branch, National Institutes of Health, Bethesda, MD. Patients and healthy controls were matched according to age and sex. Written informed consent was obtained from all subjects before testing. DNA was screened for rs12628 and rs112587690 polymorphisms by sequencing or fragment analysis, respectively.HRAS_rs12628_F: GTGGGTTTGCCTTCAGAHRAS_rs12628_R: CTATCCTGGCTGTGTCCTGPCR for rs12628 polymorphism was performed in 20 μl final volume, containing 50 ng of genomic DNA, 10 μl of Qiagen HotStarTaq Master Mix Kit  and 1 μM of forward and reverse primers with the following cycling conditions: initial denaturation at 95 °C for 10 min; 35 cycles at 95 °C for 30 s, 56 °C for 30 s and 72 °C for 30 s; final step 72 °C for 10 min. Primers were selected using Primer3 software:PCR products were then sequenced on Applied Biosystems 3730 Genetic Analyzer  and analyzed by Sequencher software .HRAS_rs112587690_F (6-FAM labeled): GTGGGTTTGCCCTTCAGATHRAS_rs112587690_R: ATATTCCGTCATCGCTCCTCPCR for rs112587690 SNP was performed in 20 μl final volume, containing 100 ng of genomic DNA, 10 μl of Qiagen HotStarTaq Master Mix Kit , and 0.5 μM of forward and reverse primers with the following cycling conditions: initial denaturation at 95 °C for 10 min; 5 cycles at 95 °C for 30 s, 57 °C for 30 s and 72 °C for 30 s; then 35 cycles at 95 °C for 30 s, 55 °C for 30 s and 72 °C for 30 s; final step 72 °C for 10 min. Primers were selected using Primer3 software:PCR products were previously sequenced on Applied Biosystems 3730 Genetic Analyzer  to confirm gene sequence and then diluted 1:100. One microliter of diluted PCR products was run on Applied Biosystems 3730 Genetic Analyzer  for fragment analysis, using 0.3 μl of GeneScan 600 LIZ Size Standard  for each reaction.Each PCR used distilled water instead of DNA as a negative control.DNA fragments were finally analyzed using Gene Mapper software (Applied Biosystems). The size of the products were P1 (145 bp), P2 (151 bp) and P3 (157 bp).Total RNA was isolated from 112 metastatic tumor samples from as many patients of the cases group. Tumor samples were from snap frozen biopsies.cDNAs were fragmented, biotinylated, and hybridized to the GeneChip Human Gene 1.0 ST Arrays . Probe normalization, background correction, Log2 transformation and summarization were performed using Robust Multi-Chip Average (RMA). Gene summary was obtained by averaging the mean of the probe values end expressed as Log2 intensity .HRAS mRNA expression values (log2 transformed) were extrapolated and evaluated according to rs12628 and rs112587690 genotypes.https://pharmgat.org/). The association between the rs12628 and rs112587690 genotypes and HRAS mRNA expression was tested by one-way ANOVA and two-tailed student's t tests. All the statistical analyses were performed using Partek software and Instat 3 software.Hardy–Weinberg equilibrium was tested by Chi-square. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated. The haplotype analysis of rs12628 and rs112587690 polymorphisms was carried out using pharmgat online tool (http://www.cbrc.jp/research/db/TFSEARCH.html).Transcription factor binding site analysis of the intronic rs112587690 sequence was carried out using online TFSEARCH online software (p = 0.07), while those frequencies were 46, 37, and 17 % in melanoma patients, respectively. A high frequency of “C” allele was found in cases compared with controls, but the difference in allele frequency was not statistically significant. The distribution of genotypes revealed a higher frequency of CC in cases compared with controls (p = 0.003).The distribution of rs12628 genotypes and allele frequency in cases and controls are shown in Table p = 0.003).To evaluate the risk of cutaneous melanoma according to rs12628 genotypes, ORs and their 95 % confidence intervals were calculated. Compared with TC + TT genotypes, CC genotype significantly associated with a 3.83-fold increased risk . The distribution of rs112587690 and its allele frequency are shown in Table p = 0.08).The rs112587690 genotype frequencies conformed the Hardy–Weinberg equilibrium in controls , while the genotype P1P1 significantly associates with cases with an 11-fold increased risk .When analyzing genotype frequencies, the genotype P1P3 resulted significantly higher in controls than in cases . Thus, individuals harboring the rs12628 TT genotype predictably carried rs112587690 homozygous P3 alleles. Conversely, individuals with rs12628 CC genotype carried the rs112587690 minor allele P1 and/or P2 in any combination . Not surprisingly, heterozygous rs12628 CT individuals segregated into two distinct rs112587690 genotypes: P1P3 and P2P3.We also examined the linkage between the rs12628 and rs112587690 polymorphisms in all 141 cases and 118 controls. Consistent with the literature , in everHRAS gene, thus we sought to examine the level of HRAS mRNA in tumor tissues according to the different genotypes of rs12628 and rs112587690 polymorphisms. Toward this goal, we extrapolated the log2 intensity values from microarray analysis and evaluated the possible differential expression by one-way ANOVA and unpaired Student’s t test. The difference in HRAS mRNA expression level tended to be higher in metastases of patients carrying rs12628 CC genotype than in those carrying CT and TT genotypes, but this difference was not statistically significant   and one for ADR1 .Different polymorphisms could affect the binding site sequences for several transcription factors. In order to investigate the possible biological meaning of rs112587690 polymorphism, TFBS (transcription factor binding site) prediction analysis of the polymorphic region was carried out by using online TFSEARCH program. Compared with P1 and P2 allele sequences, P3 allele sequence turned out to have an additional binding site for RAS genes have been identified such as minisatellites and acquired mutations in various cancers including melanoma. In this study, we assessed germline variants of HRAS in the context of cutaneous melanoma; rs12628 was frequently observed and considered an informative SNP. Thus, we conducted a case–control polymorphic study of HRAS rs12628 to assess the role of this SNP in cancer.Several molecular alterations in the p = 0.003), with a 3-fold increased risk of melanoma in CC individuals. Thus, HRAS rs12628 represents a strong susceptibility factor for the development of melanoma. However, these epidemiological data do not reveal the mechanisms by which HRAS rs12628 SNP modifies melanoma risk. Acquired amino acid mutations in the hotspot codons 12, 13, 61, and 146 prolong the GTP-bound activated state of the HRAS product; in contrast, SNP rs12628 is located in a wobble base position, that should not lead to alterations in protein structure. It is conceivable that this probably nonfunctional polymorphism is linked to other polymorphic sites in functional intron regions of HRAS.Assuming a recessive genetic model of inheritance, a statistically significant result was found when comparing carriers of the homozygous mutant C-allele to heterozygotes CT and wild-type carriers TT , while genotypes P1P3 resulted significantly associated with control group . Thus, HRAS rs112587690 represents an additional susceptibility factor for the development of melanoma. Moreover, according to the report aforementioned [D′ = 1). The strong linkage disequilibrium observed between the two polymorphisms could reflect a differential transcriptional regulation of HRAS gene, according to the specific genotype.A potential linkage candidate is the hexanucleotide repeat located about 80 bp upstream of the 5′-end of exon 1 (rs112587690). Sol-Church et al.  observedHRAS gene, and thus we sought to examine the level of HRAS mRNA in the tumor tissues according to rs12628 and rs112587690 genotypes. Overall, melanoma metastases from patients carrying rs12628 CC genotype trended toward higher HRAS mRNA expression, followed by those from patients carrying TT and TC genotypes, respectively. However, these differences were not statistically significant   and one for ADR1  were predicted in the P3 allele sequence as compared to P1 and P2 alleles. Further functional studies on the role of these transcription factors are needed to better understand the importance of rs112587690 polymorphism as a regulator of HRAS transcription.Whereas recognition of functional variants in coding regions is easy, detecting functional change in non-coding DNA is more difficult because there is no clear connection between nucleotide differences and function for these sequences, and regulatory regions can be located far from the coding region . NonetheHRAS polymorphism rs12628 may be a risk factor for the development of melanoma in the Caucasian North American population possibly through the linkage to rs112587690 polymorphic site. Additional studies with large samples are needed to confirm these results.This study provides evidence that the


APOM T-778C polymorphism and serum lipid levels and the risk of CAD in the Chinese population.The apolipoprotein M (APOM) T-778C gene polymorphism has been associated with serum lipid levels and the risk of coronary artery disease (CAD), but the results are inconclusive. The purpose of this meta-analysis was to detect the association between the Databases of MEDLINE, EMBASE, the Cochrane Library and CNKI were systematically searched. Data were extracted using standardized methods. The association was assessed by mean difference (MD) with 95% confidence intervals (CI) or odds ratio (OR) with 95% CI.P < 0.0001) and low-density lipoprotein cholesterol (LDL-C)  than TT group. There was no difference in the levels of triglyceride  and high-density lipoprotein cholesterol  between TT and CT+CC groups. Pooled effects showed that CAD group had higher CT+CC genotype frequency than control group .Ten studies with 4,413 patients were included in this meta-analysis. Pooled effects indicated that CT+CC group had higher levels of total cholesterol (TC) (MD:-0.36, 95% CI: -0.53 – -0.19, APOM T-778C polymorphism and the risk of CAD in the Chinese population, the CT+CC genotype is associated with increased risk of CAD.The results of the current meta-analysis show that the CT+CC group has higher levels of TC and LDL-C than the TT group. Moreover, there is also a prominent association between  Coronary artery disease (CAD) continues to be the leading cause of morbidity and mortality among adults nowadays . Many stAssociation of different genes and CAD and/or dyslipidemia has been widely examined. Recently, apolipoprotein M (APOM) gene has been reported relevant to CAD and dyslipidemia . APOM geAPOM T-778C (rs805296) is valid in the Han Chinese and associated with serum lipid levels and the risk of CAD, but the results are inconclusive [Recent studies have showed that the nclusive -23. It mAPOM T-778C polymorphism and serum lipid levels and/or the risk of CAD and published in English or in Chinese before May, 2013 were identified by comprehensive computer-based searches of MEDLINE via PubMed (from 1950 to May 2013), EMBASE (1980 to May 2013), the Cochrane Library database  and China National Knowledge Infrastructure (CNKI). The following key words were used: “Apolipoprotein M,” “APOM,” “rs805296 (T-778C) polymorphism”, “dyslipidemia” and “serum lipid level”, “coronary artery disease”. The above search strategy described was used to obtain titles and abstracts of studies that may have been relevant to this review. The titles and abstracts were screened independently by two authors (Z Zhang and G Chu), who discarded studies that were not applicable. When multiple reports from the same patients were found, only the study with the most complete data set was included in the meta-analysis. But duplicate patients of different articles that have different types of data of outcomes were included both. Any disagreements were arbitrated by discussion with the third reviewer (R-X Yin).All studies that reported the association between the Two investigators reviewed all identified studies independently to determine whether an individual study was eligible for inclusion. The selection criteria for studies to be considered for this meta-analysis were as follows: (1) case–control studies published in peer-reviewed journals with full available text in English or in Chinese; (2) the APOM gene T-778C polymorphism and serum lipid levels and the risk of CAD; (3) reporting at least one relevant outcomes of association between genotype and serum lipid levels and the risk of CAD, serum lipid levels including TC, HDL-C, LDL-C, and TG. Excluded studies: (1) studies in which it was not possible to extract data from the published results and from the authors; and (2) studies that did not report appropriate outcomes were also excluded.(1) Relationship between serum lipid parameters and genotypes; (2) Relationship between the risk of CAD and genotypes; (3) Genotype freguency: TT and CT+CC; (4) Serum lipid parameters: TC, TG, HDL-C, and LDL-C.Two investigators (Z Zhang and G Chu) independently extracted data according to the author details and the following information was extracted from each study: first author, year of publication, sample size, diagnostic criteria, study design, characteristics of controls, genotype information , relationship between genotypes and serum lipid parameters and the risk of CAD. Discrepancies were resolved by discussion. When repeated publications of the same trial were identified, data were extracted from the repeated publications and reported as a single trial.The Newcastle-Ottawa Scale (NOS)  was usedP > 0.05) [). We examined the contrast of genetic model (TT vs. CT+CC) in serum lipid levels and genetic model (CT+CC vs. TT+CT+CC) in the risk of CAD. Continuous variables were expressed as mean difference (MD) with 95% confidence intervals (CI). Dichotomous outcomes of the numbers of CT+CC and TT+CT+CC genotypes in CAD/control values were expressed as odd ratio (OR) with 95% CI. The pooled effects were calculated using fixed effects models when there was no significant heterogeneity but the random effects model was analyzed to ensure robustness of the model chosen and susceptibility to outliers, or using random effects models when there was significant heterogeneity but the fixed effects model was analyzed to ensure robustness of the model chosen and susceptibility to outliers. The point estimate of the MD or OR was considered statistically significant at the 2-tailed P ≤ 0.05 level. Heterogeneity was analyzed using a chi-square test on N-1 degrees of freedom [I2 values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity; respectively. Sensitivity analyses were performed omitting a single study at a time or analyzed another model chosen. If enough studies were identified, funnel plots were to be used to investigate reporting biases [Allele frequencies of each study were determined by the allele counting method. Hardy–Weinberg equilibrium (HWE) for each single nucleotide polymorphism was assessed for the controls in each study using Pearson’s Square ( > 0.05) . We carr freedom . I2 valug biases .Ten studies -23, 5 inThe main characteristics of each study are shown in Table The quality of all included studies was assessed by NOS Table . Most stAPOM T-778C genotypes in each group and all P-values of HWE testing are shown in Table APOM T-778C polymorphism in all eligible studies was consistent with HWE (P > 0.05).Frequencies of the P < 0.0001; heterogeneity test x2 = 56.34, P < 0.00001, I2 = 75%). There was no difference in the levels of TG between TT and CT+CC groups .The eligible compared groups were pooled with fixed effects models and the data of CT+CC and CC+CT+TT groups in the CAD/control value and the pooled effects are shown in Figure Sensitivity analyses were performed to assess the contribution of each study to the pooled estimate and by excluding individual studies one at a time and recalculating the pooled MD or OR estimates for the remaining studies. Eliminating the studies with more than 300 patients or less than 100 patients in each group did not substantially change the pooled point estimate, which indicates the reliability of our results. What is more, performing transition of model also did not substantially change the pooled point estimate.I2 value of heterogeneity was greater than 50% and the heterogeneity test: P value was less than 0.10 in model TT vs. CT+CC in the overall populations, which indicated statistically significant heterogeneity among the studies. In order to explore the sources of heterogeneity, the studies were stratified by cases and controls and subgroup analyses were performed. However, heterogeneity still existed in the outcomes of TC  and OR of total of CAD risk (P < 0.00001) were large effect. All these made our conclusion more robust.In the present study, we included ten studies and all of the subjects were the Chinese populations. Baseline characteristics of two comparison groups of included studies were substantially similar. All included studies were consistent with HWE. The quality of the included studies that associated between polymorphism and CAD risk was assessed by NOS and most studies were of medium or high quality. In addition, heterogeneities of pooled effects of HDL-C, LDL-C and CAD were low. MD of total of TC ( Heterogeneity analysis showed that the polymorphism suggested significant heterogeneity in the outcomes of TC in the overall populations. To explore the sources of heterogeneity, we performed subgroup analyses, but heterogeneity still existed in the outcomes of TC. This may be due to China being a large country with multiethnic country. Different groups of the included studies had different genetic background and environmental factors. It is well known that both serum lipid levels and CAD are affected by genetic and environmental factors, such as dietary patterns, lifestyle, obesity, physical inactivity. Moreover, pharmaceuticals, age, gender, hypertension are also associated with serum lipid levels .Some limitations of this meta-analysis should be discussed. First, this meta-analysis focused only on papers published in English and Chinese and the ones that reported in other languages may bias the present results. Second, the meta-analysis cannot be corrected the bias of each study in the outcomes of TC, and may generate a statistical conclusion with more power and precision. In addition, gene-gene and gene-environment interactions should also be considered in the analysis.APOM T-778C polymorphism and serum lipid levels or the risk of CAD.Therefore, it is necessary to conduct large sample studies using standardized unbiased genotyping methods, homogeneous CAD patients and well- matched controls. Moreover, gene-gene and gene-environment interactions should also be considered in the analysis. Such studies taking these factors into account may eventually lead to better, more comprehensive understanding of the association between the APOM T-778C polymorphism and the risk of CAD in the Chinese population, and the CT+CC genotype was associated with increased risk of CAD.The results of the current meta-analysis showed that the CT+CC group had higher levels of TC and LDL than the TT group, and there was no difference in the levels of HDL and TG between the TT and CT+CC groups. Moreover, there a prominent association between the The authors declare that they have no competing interests.ZZ and GC conceived the study, participated in the design, collected the data, performed statistical analyses, and drafted the manuscript. RXY conceived the study, participated in the design, and helped to draft the manuscript. All authors read and approved the final manuscript.


Many epidemiological studies have found a positive association between periodontal disease (PD) and the risk of preeclampsia, but the magnitude of this association varies and independent studies have reported conflicting findings. We performed a meta-analysis to ascertain the relationship between PD and preeclampsia.The PubMed database was searched up to January 12, 2013, for relevant observational studies on an association between PD and the risk of preeclampsia. Data were extracted and analyzed independently by two authors. The meta-analysis was performed using comprehensive meta-analysis software.Thirteen observational case-control studies and two cohort studies, involving 1089 preeclampsia patients, were identified. Based on a random-effects meta-analysis, a significant association between PD and preeclampsia was identified .Although the causality remains unclear, the association between PD and preeclampsia may reflect the induction of PD by the preeclamptic state, or it may be part of an overall exaggerated inflammatory response to pregnancy. Larger randomized controlled trials with preeclampsia as the primary outcome and pathophysiological studies are required to explore causality and to dissect the biological mechanisms involved. Periodontal disease (PD) is a chronic destructive inflammatory disease affecting the tooth-supporting tissues, and it is one of the most prevalent chronic infections in humans. At least 35% of dentate adults aged between 30 and 90 years in the United States experience PD An improved understanding of this issue may have important public health and clinical implications given the possibility that preventing and treating PD may reduce the incidence of preeclampsia. The objectives of this study were (1) to evaluate the inconsistent results of published observational studies on the association between PD and the risk of preeclampsia by conducting a meta-analysis and (2) to gain a more robust understanding of the association between PD and the risk of preeclampsia.We initially identified publications that investigated the association between PD and the risk of preeclampsia by searching the PubMed and Embase databases from their inceptions through February 10, 2013. The following search terms were used: (1) “periodontal disease” or “periodontitis” or “periodontal” or “gum disease” or “periodontium”, and (2) “pregnancy outcomes” or “pregnancy complications” or “preeclampsia” or “pregnancy hypertension”. The resulting papers were first screened by title and abstract. Full-text papers were obtained when the studies fulfilled the selection criteria, as described below. Full-text analyses were independently performed by two reviewers. Case reports, letters, reviews, abstract-only studies and commentaries were excluded from the search.We included any study that met all of the following criteria: (1) the study had a cross-sectional, case-control or cohort design; (2) clear diagnostic criteria for PD and preeclampsia were established; (3) the association between PD and the risk of preeclampsia was investigated; and (4) the odds ratios (ORs)/risk ratio  and the corresponding 95% confidence intervals (CIs), or the number of events required to calculate them, were reported. Two authors independently evaluated the eligibility of all studies retrieved from the databases. Disagreements were resolved by discussion or in consultation with a third author.Two reviewers independently extracted data regarding the characteristics of each study using a standardized data collection form. Data were recorded as follows: first author’s last name, year of publication and country of origin; number of participants with PD and total number of participants; ascertainment of PD; assessment of preeclampsia; and statistical adjustments for confounding factors. Any disagreements were resolved by consensus.The quality of each included study was independently evaluated by the three authors using the Newcastle-Ottawa Scale (NOS) 2 statistic 2 was considered statistically significant for heterogeneity. The fixed- and random-effect models were adapted to calculate the pooled estimate where appropriate. To assess whether publication bias may have impacted the statistical results, a funnel plot was created, and Egger’s test was performed The pooled OR with 95% CI between PD and preeclampsia was used to estimate the effect sizes. We conducted a stratified analysis for the study design. Statistical heterogeneity among the studies was assessed using Cochran’s Q test and the IThe detailed search procedures are summarized in 2 = 69.75%).The pooled ORs from the 13 case control studies and two cohort studies are shown in A subgroup meta-analysis was performed by study design . A positP value for Egger’s regression asymmetry test was 0.14, which indicates a low probability of publication bias  and/or diastolic pressure (≥90 mmHg) and proteinuria (≥300 mg/24 h), after 20 weeks of gestation. This condition is potentially dangerous for both the mother and the fetus. PD is considered a novel risk factor for preeclampsia, in addition to Periodontal disease is initiated by oral microorganisms, but it is believed that severe periodontal breakdown is mediated by the inflammatory response of the host. The inflammatory response may not be limited to the periodontal area. It has been proposed that daily episodes of bacteremia or dissemination of bacterial endotoxins from the periodontal focus may induce systemic activation of the inflammatory response. Bacteria or bacterial endotoxins in the systemic circulation may induce pro-inflammatory cytokine production. These cytokines then further activate the inflammatory response, which results in a chronic low-grade systemic up-regulation of the inflammatory molecules involving IL-6 and C-reactive protein (CRP) Our meta-analysis has several strengths. First, many cases were included, which provides solid evidence for evaluating the epidemiologic association between PD and preeclampsia risk. Second, the included studies were conducted in different countries, which makes the results more generalizable. Third, based on the NOS, all studies included in this meta-analysis were of high or intermediate quality.Our meta-analysis has several limitations. First, cohort studies and case-control studies may be susceptible to detection bias, and recall and selection biases are often present in case-control studies. Second, as the studies included in this meta-analysis were all observational studies, the observed positive association between PD and the risk of preeclampsia may have resulted from unmeasured factors. The only slight attenuation of effect size upon adjustment for age, body mass index (BMI)/obesity, smoking and alcohol consumption suggests that the association between PD and preeclampsia risk is robust and less likely to be greatly attenuated by unmeasured factors, although the residual confounding effects of the measured variables, particularly BMI/obesity, may not be completely removed. Fourth, none of the 15 studies selected in our meta-analysis provided the degree of PD and risk of preeclampsia; therefore, we were unable to conduct a dose-response analysis to assess the relationship between these variables more precisely. Fifth, the prevalences/incidences of preeclampsia in developing countries  are presumably much higher than those in developed countries , but we could not obtain current relevant data to verify this assumption.In summary, our meta-analysis suggests that PD may increase the risk of preeclampsia. Further investigations should assess the underlying biological links between PD and preeclampsia.


HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs) and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include  Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs. It is defined by a clinical syndrome associated with moderate-to-severe asthma and eosinophil inflammation in the upper and lower airways, resulting in chronic rhinosinusitis and asthma . AdditioThe dysregulation of arachidonic acid metabolism also accounts for the susceptibility to AERD. Metabolites involved are prostaglandins (PGs), leukotrienes (LTs), and thromboxane (TBX). Inhibition of COXs by acetyl salicylic acid (ASA) in the respiratory tract alters arachidonic acid metabolism, leading to a reduction in PGE2. This may increase AERD susceptibility by overproduction of CysLTs , 5. The LTC4S −444A  >  C promoter polymorphism and AERD. In the population investigated (Polish), the C allele was identified as a risk factor; however, this finding was not replicated in Japanese, American, or Korean populations  was significantly higher in AERD than in ATA, suggesting a possible contribution of ALOX5 in AERD [CysLTR2, the frequencies of minor alleles for −819T  >  G, 2078C  >  T, and 2534A  >  G were significantly higher in the AERD group [Based on evidence showing a close association of leukotrienes and AERD, initial research was performed on the association between ulations –15. SNPs in AERD . We idenTBXA2R, −4684T  >  C, and +795T  >  C, were shown to be associated with the phenotype of AERD in a Korean population [PTGER2) was associated with the risk of AERD by decreasing the level of transcription, resulting in a reduction of the “PGE2 braking” mechanism of inflammation and involvement in the molecular mechanism underlying AERD in the Japanese population [PTGER3) may be an important genetic factor for aspirin intolerance in Korean asthmatics [DPB1*0301 was identified as a strong marker for AERD, because patients with this allele showed typical characteristics of AERD including a decreased forced expiratory volume in 1 s (FEV1) and increased prevalence of rhinosinusitis with nasal polyps [It has been suggested that AERD is associated with both COX1 and COX2. Aspirin inhibits both of these proteins, with a greater effect on COX1. COX2 expression was downregulated in nasal polyps collected from AERD patients . Decreaspulation , 23. Thepulation . A furththmatics . The huml polyps , as prevl polyps .CRTH2 −466T  >  C polymorphism, could increase serum and cellular eotaxin-2 production by lowering CRTH2 expression, leading to eosinophilic infiltration in AERD patients [CCR3 −520T  >  C was significantly associated with AERD patients where mRNA expression was also significantly increased after ASA provocation [IL-13 Arg110Gln may be associated with an increased eosinophil count and eotaxin-1 level, leading to an increase in eosinophilic inflammation in the upper and lower airways of patients with AERD [Eosinophil infiltration into the upper and lower airways is a key feature of AERD. Increased numbers of eosinophils and mast cells have been observed in the bronchial mucosa of AERD , 29. Recpatients . A furthvocation . IL-13 pith AERD  (Table 1TLR3) gene, TLR3 −299698G  >  T and 293391G  >  A, were associated with the AERD phenotype. TLR3 recognizes dsRNA, activates nuclear factors, and increases interferon-gamma, which is a signal to other cells and increases antiviral defenses. As functional deterioration of TLR3 can predispose individuals to increased susceptibility to viral infections, the detection of TLR3 polymorphisms may be informative for risk assessment in AERD susceptibility [Szczeklik has hypothesized that AERD develops as the result of chronic viral infection . Viral rtibility . The sugUBE3C) has been recently studied in a Korean population and indicated that rs3802122 and rs6979947 is associated with AERD [KIF3A) gene and its polymorphism might have an effect on AERD, because rs3756775 revealed a significant association with the percentage decline in FEV1 after aspirin provocation [CACNG6) gene encodes a protein that stabilizes the calcium channel. CACNG6 has been studied in AERD, which revealed that rs192808C  >  T may be associated with the risk of AERD in a Korean population [The ubiquitin-proteasome pathway-related gene  have recently emerged as a technology that can predict genetic variations across the genome associated with human diseases and clinical responses to drug treatment. Recently, GWAS for asthma and related phenotypes have reported several susceptible genes. Candidate gene approaches have been used for most of the genetic association studies of AERD. GWAS suggested that the nonsynonymous tructure .LTC4S −444A  >  C synthesis increased the lower level of FEV1 after lysine ASA inhalation [TBXA2R 795T  >  C polymorphism was associated with HLA DPB1*0301 in AERD patients compared with ATA [TGF-beta1-509C/T and IL-10-1082A/G polymorphisms on the phenotype of AERD was noted when stratified by the presence of rhinosinusitis [B2ADR −46A  >  G, CCR3 −520T  >  G, CysLTR1 −634C  >  T, and FCER1B −109T  >  C [Gene-gene interactions have also been proposed in the pathogenesis of AERD, and a few studies indicated that the genetic effects of CysLTs and halation . TBXA2R with ATA . Recentl9T  >  C . These fAERD often produces a moderate-to-severe phenotype; however, diagnosis in these patients is challenging despite the availability of various techniques. A hypothesis has been put forward, mostly focused on the overproduction of CysLTs and arachidonic acid pathways. Most of the genetic studies have been performed using techniques such as GWAS and the candidate gene approach. However, replication studies in different ethnic groups will be essential to validate the reported data and apply this knowledge in clinical practice. Future areas of investigation should focus on identification of biomarkers for early diagnosis with various diagnostic techniques. These genetic studies will be able to extend our understanding about the molecular genetic mechanism of AERD and to find a genetic marker for predicting drug responses or hypersensitivity reactions. Furthermore, this will be helpful for the determination of new diagnostic tools and therapeutic interventions.


Three common X-ray repair cross-complementing groups 1 (XRCC1) polymorphisms, Arg399Gln, Arg194Trp, and Arg280His, have been reported to be implicated in the development of leukemia. However, previous results from different studies were inconsistent. Consequently, we performed a meta-analysis in order to accurately evaluate the association between XRCC1 Arg399Gln, Arg194Trp, and Arg280His polymorphisms and leukemia risk.Through computerized searching of PubMed, ISI Web of Knowledge, Cochrane, EBSCO, and OpenGrey databases, and manually searching relevant references, a total of 19 studies with 3387 cases and 6168 controls for Arg399Gln (G>A) polymorphism, 12 studies with 2043 cases and 4550 controls for Arg194Trp (C>T), and 6 studies with 1445 cases and 1905 controls for Arg280His (G>A) were collected to perform meta-analysis and stratified analysis to explore the associations between these variants and leukemia susceptibility. Based on three genetic models, the codominant model, dominant model and recessive model, odds ratios (ORs) as well as their 95% confidence intervals (CIs) were used to evaluate the association strength between XRCC1 genotypes and leukemia risk.With respect to overall leukemia susceptibility, no association was detected. In stratified analyses by tumor type, Arg399Gln was associated with higher acute lymphoblastic leukemia (ALL) risk . Additionally, Arg399Gln, Arg194Trp, and Arg280His may influence the susceptibilities of some leukemia type and race populations.This meta-analysis indicates these three polymorphisms of XRCC1 do not associate with overall leukemia risks but could be associated with the risks for some specific subgroups. Leukemia is one of the most common human cancers, with an estimated 48610 new cases and 23720 deaths expected in the US in 2013 Impaired DNA repair may be associated with increased susceptibility to human cancers Computer bibliographic searches through PubMed, ISI Web of Knowledge, Cochrane, EBSCO, and grey literature database OpenGrey were conducted using the keywords: “leukemia,” “leukaemia” and “polymorphisms,” “genotypes,” “variants,” and “XRCC1,” “X-ray repair cross-complementing groups 1,” with the final search completed in May 2013. Studies from the references of the related reports were checked. Articles in all languages were searched to ensure the relevant studies were not missed. The following inclusion criteria were applied: (1) case-control studies or nested case-control studies within cohort studies, if any (2) studies evaluating association between XRCC1 polymorphism and leukemia risk, (3) full text reports which including enough data to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The exclusion criteria were as follows: (1) duplicated reports, (2) reviews or meta-analyses, if they were performed without additional eligible studies; otherwise, the additional eligible study was included in our meta-analysis, (3) if the same population was used in multiple studies, only the most complete or latest study was selected for further analysis.According to the study identification criteria, the available studies were reviewed, selected, and the following information from the eligible studies was extracted: first author’s last name, publication year, country, leukemia type, number of case and control subjects, ethnicity, control subjects source population, and genotype numbers of cases and controls.Critical quality assessment of the included studies was performed by Effective Public Health Practice Project Quality Assessment Tool (EPHPP). With this tool, assessments of the risk of bias or methodological quality were made separately for six individual domains: selection bias, study design, confounders, blinding, data collection method, and withdrawals and drop-outs. The comprehensive dictionary for the assessment tool was used to guide the rating of the studies. Each domain was rated as strong, moderate, or weak. The study quality was then evaluated as strong, moderate, or weak if there were no, one, or two or more in total weak ratings for all the domains, respectively χ2 test. The strength of association between XRCC1 Arg399Gln, Arg194Trp, and Arg280His polymorphisms and leukemia risk was measured by odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). We used codominant, dominant, and recessive genetic models to assess the pooled ORs. For both Arg399Gln and Arg280His (G>A) polymorphisms, the codominant model included homozygous comparison of AA vs. GG and heterozygous comparison of GA vs. GG, the dominant model was AA+GA vs. GG, and the recessive model was AA vs. GA+GG. For Arg194Trp (C>T) polymorphism, the codominant model included homozygous comparison of TT vs. CC and heterozygous comparison of CT vs. CC, the dominant model was TT+CT vs. CC, and the recessive model was TT vs. CT+CC. Stratified analyses were performed by race, control source, and tumor type. Due to the high heterogeneity across the studies, the random effects model based on the DerSimonian and Laird method was applied www.OpenEpi.com). Statistical analysis was conducted in R 2.15.2 using “meta” package Statistical analyses were performed as described previously Searches of PubMed, ISI Web of Knowledge, Cochrane, EBSCO, and OpenGrey databases and manually searching references returned 154 studies. Among them, 135 reports were excluded for the following reasons: 55 were duplications, 42 were irrelevant to XRCC1 polymorphisms and leukemia risk, 29 did not provide enough genotype information, and 8 were reviews or meta-analyses., In addition, studies that involve the same population as another eligible study were excluded to avoid bias Meta-analysis and relevant subgroups analysis by tumor type, race and control sources were conducted to examine the association between XRCC1 Arg399Gln (G>A), Arg194Trp (C>T), and Arg280His (G>A) polymorphisms and leukemia risk in three genetic models. Stratified analysis by race and control sources in each leukemia type and by etiology in AML was further performed to explore the possible associations. The analyses results were shown in P  =  0.04; Begg’s test, P  =  0.12) in the codominant heterozygous comparison (GA vs. GG) (other data not shown). We repeated meta-analysis with the “trim and fill” method to adjust publication bias in this genetic model. The conclusion was not influenced, which indicated the robustness our conclusions (data not shown). In the stratified analysis by racial descent, increased risk of leukemia was found among Asians , and the unknown or mixed race subgroup .In the overall analysis, no statistically significant association between XRCC1 Arg399Gln polymorphism and leukemia susceptibility was observed in three genetic models. A very mild publication bias was detected by Egger’s test   and amonXRCC1 Arg194Trp was not associated with the leukemia susceptibility in the overall population or in different race and control source subgroups. Publication bias does not exist across the studies (data not shown). Arg194Trp worked as a risk factor in the AML Asians  albeit there was only one study for this race subgroup.P  =  0.04, Egger’s test P  =  0.02), and the recessive model  (other data not shown). Adjusting these two models by “trim and fill” method did not influence the conclusion (data not shown).As for Arg280His polymorphism, no statistically significant association was present in any genetic model or subgroup except for among the secondary and therapy-related AML codominant model homozygous comparison , and the recessive model . Begg’s test and Egger’s test showed publication bias in the main meta-analysis in the codominant homozygous comparison , and the unknown or mixed race subgroup  while no such effect was found among Caucasians . The finThe predisposition of each leukemia type could be differentially influenced by genetic factors. We performed stratified analysis by leukemia type in order to clarify the role of XRCC1 polymorphisms in the development of individual types of leukemia . In the α significance criterion 0.05 in the target population. Because the effects of the Arg194Trp and Arg280His polymorphisms on leukemia risk are weak (The advantages of this meta-analysis are that it is the most complete and the information from the eligible studies is utilized as much as possible through genetic model and stratified analysis. However, there are several limitations in this study. First, expression of specific genes is highly regulated by a transcriptional control mechanism requiring transcription factors-gene promoter interaction Taken together, results from this meta-analysis demonstrate that XRCC1 Arg399Gln, Arg194Trp and Arg280His polymorphisms might not be associated with overall leukemia risk. However, these polymorphisms might potentially be protective factors or risk factors in specific leukemia types or among particular ethnicities.


Publications regarding the associations of toll-like receptor 2 (TLR2) G2258A and T597C polymorphisms with pulmonary tuberculosis (PTB) susceptibility are inconsistent. A meta-analysis was conducted to investigate the relationship between TLR2 G2258A and T597C polymorphisms with PTB susceptibility.A systematic search was performed for published studies on the relationship between TLR2 polymorphisms and PTB susceptibility. Information was gathered from each eligible study, and statistically analyzed.P<0.001, GA+AA vs. GG: OR  = 2.69, 95% CI = 1.49–4.87, P = 0.001). In the subgroup analyses, the 2258G allele and 2258GG genotype also exhibited a protective effect of PTB risk in Asians , while no associations were observed in Caucasians. No significant associations between T597C polymorphism and PTB were found in the allele model , co-dominant model , recessive model , or dominant model . The associations of T597C polymorphism with PTB susceptibility, in the ethnic-specific analyses, were still not significant.6 eligible studies, totaling 1301 cases and 1217 controls on G2258A genotypes, and 8 studies, totaling 2175 cases and 2069 controls on T597C genotypes, were included in the analysis. TLR2 2258G allele and 2258GG genotype were found to be associated with decreased PTB susceptibility (A vs. G: OR  = 3.02, 95% CI: 2.22–4.12, TLR2 2258G allele may provide protective effects against PTB susceptibility, particularly among Asians, whereas TLR2 T597C polymorphism might not be associated with PTB susceptibility. Mycobacterium tuberculosis (M. tuberculosis), leads to a considerable global health burden, especially in Southeast Asia M. tuberculosis, with 1% currently infected. However, only 10% of those who are infected advance to clinical diseases, such as pulmonary tuberculosis (PTB) M. tuberculosis is still unclear. Until now, multiple factors have been reported to affect the outcome of M. tuberculosis infection, including age, gender, ethnicity, etc. The host genetic factors are assumed to play a critical role in tuberculosis pathogenesis, through impact on the gene expression of cytokines and chemokines, which are implicated in the host immune response. Furthermore, both animal models and segregation analyses have been performed to support the idea of genetic susceptibility to PTB Tuberculosis (TB), mainly caused by M. tuberculosis. After recognition of bacterial lipoproteins, TLR2 activates the MyD88 adaptor-like protein , and triggers a signaling pathway, which induces further immune response M. tuberculosis.Toll-like receptors (TLRs), the vital pattern recognition receptors (PRRs), are composed of 13 trans-membrane proteins, and are mainly expressed in immune cells, such as dendritic cells and epithelial cells. TLRs play a vital role in the first line of host defense. They induce adaptive immune reactions against microbial pathogens Although previous studies have debated over the contribution of TLR2 G2258A and T597C polymorphisms to PTB, the small sample sizes and inadequate statistical power of these studies do not offer robust results. Therefore, we performed a meta-analysis to investigate the relationship between TLR2 G2258A and T597C polymorphisms with PTB susceptibility.A systematic search was performed for published studies on the relationship between TLR2 polymorphisms and PTB susceptibility without language restriction. PubMed and Embase, as well as two Chinese databases , were utilized to search the available articles published from January 2000 to March 2013. The search terms were as follows: “toll-like receptor 2” or “TLR2”, “polymorphisms” and “pulmonary tuberculosis”. The references of selected articles and review articles were also examined to identify additional eligible studies.Inclusion criteria: (1) case-control studies, which evaluated the relationship between TLR2 G2258A and T597C polymorphisms with tuberculosis susceptibility; (2) available genotype frequencies from the studies; (3) original articles published in peer-reviewed journals. Exclusion criteria: (1) studies with non-specification of sample origins; (2) studies with insufficient or duplicate data; (3) studies with same author from similar origins.The following information was sought independently by two investigators from each eligible study according to the criteria listed above: first author's surname, year of publication, ethnicity, genotyping method, size of cases and controls, and size of cases and controls with TLR2 G2258A and T597C genotypes. For those studies that included subjects of PTB, extrapulmonary tuberculosis, and tuberculosis meningitis, only the numbers and genotype frequencies of PTB cases and healthy controls were extracted. For studies that included subjects of different ethnic groups, data were extracted for each group.P<0.1 was considered statistically significant. When the effect was assumed to be lack of heterogeneity, the fixed-effects model (Mantel-Haenszel method) was used to calculate the pooled OR and 95% CIs; otherwise, the random-effects model (DerSimonian-Laird method) was used. Sensitivity analysis of the meta-analysis was performed by removing each single study step by step to assess the stability of the results. An estimate of potential publication bias was carried out by funnel plot when at least five papers were included. This was performed by plotting the log [OR] versus the standard error of log [OR] for each included study. Every circle dot represents a separate study for the indicated association. The perpendicular line represents the meta-analysis summary estimate. In the absence of publication bias, studies will be distributed symmetrically on the left and right of the perpendicular line. The funnel plot asymmetry was also assessed by Egger's regression and P<0.05 was considered representative of statistically significant publication bias. A chi-square test for goodness of fit was used to test Hardy-Weinberg equilibrium (HWE) in controls, and a P-value of <0.05 was considered significant. All analyses were done using Review Manager . All P-values were two-sided.The crude odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the association of TLR2 G2258A and T597C polymorphisms, with PTB risk for each study, based on extracted data. Subgroup analysis was also performed to assess the ethnic-specific effect. The chi-square based on Q statistic test was used for the assessment of heterogeneity and The search using PubMed, Embase, and two Chinese databases  yielded 239 articles. Of these, 222 articles were excluded by reviewing the titles and abstracts. The remaining 17 articles were reviewed in detail and 5 of them were eliminated according to the inclusion and exclusion criteria. As a result, a total of 12 articles P<0.001) (P = 0.001)  . Similar= 0.001) .P<0.001) and the dominant model . However, no significant association was identified in Caucasians .Subgroup analyses were performed to assess the ethnic-specific PTB susceptibility in Asians and Caucasians. Significant associations were observed in Asians both in the allele model  , the recessive model , or the dominant model   , the co- = 0.51) .P = 0.84), the co-dominant model  the recessive model , or the dominant model .We further restricted the ethnic-specific analyses to Asians, and the associations of T597C polymorphism and PTB susceptibility were still not significant in the allele model . Similarly, no publication bias was detected for associations of T597C polymorphisms with PTB.Individual studies in the meta-analysis were sequentially deleted to reflect the influence of each study to the pooled OR. For all allele or genotype comparisons, the pooled ORs and 95% CIs were not qualitatively different (data not shown). The shapes of the funnel plots for these polymorphisms were symmetrical in all compared models . This helped to conclude that G2258A carriage of mutant A allele significantly increased the PTB susceptibility, which is consistent with a previous study There were also some limitations in our study. Firstly, the articles included in our meta-analysis were restricted to geographically distinct populations, thus limiting the generalizability of our conclusions. In addition, we were unable to obtain sufficient data related to age, gender, drinking, smoking and other factors, in order to perform a stratified analysis in this study. Secondly, the gene-gene and gene-environment interactions could not be taken into account in our analysis. Therefore, the relationship between TLRs polymorphisms and PTB should be confirmed in future studies.In conclusion, the result of our meta-analysis demonstrated that the TLR2 2258G allele may provide protective effects against PTB susceptibility, particularly among Asians. However, the TLR2 gene T597C polymorphism showed no significant association with PTB susceptibility. Although PTB is not solely a result of genetic factors, our conclusion would support the hypothesis that potentially functional polymorphisms in TLR2 may increase or decrease PTB and allow further investigation of TLRs variants for new therapies of PTB infection.Figure S1Forest plots of the association between TLR2 G2258A polymorphism and PTB susceptibility in the allele model.(TIF)Click here for additional data file.Figure S2Forest plots of the association between TLR2 G2258A polymorphism and PTB susceptibility in the dominant model.(TIF)Click here for additional data file.Figure S3Forest plots of the association between TLR2 T597C polymorphism and PTB susceptibility in the allele model.(TIF)Click here for additional data file.Figure S4Forest plots of the association between TLR2 T597C polymorphism and PTB susceptibility in the dominant model.(TIF)Click here for additional data file.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


The Ser326Cys polymorphism in this gene may influence its repair ability and thus plays a role in carcinogenesis. Several case-control studies have been conducted on this polymorphism and its relationship with the risk of hepatocellular carcinoma (HCC) among East Asians. However, their results are inconsistent.The hOGG1 Ser326Cys polymorphism with HCC risk among East Asians. PubMed, EMBASE, SCI, BIOSIS, CNKI and WanFang databases were searched. A random-effect model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Analyses were conducted for additive, dominant and recessive genetic models.We performed a meta-analysis of published case-control studies assessing the association of the hOGG1 Ser326Cys polymorphism with HCC risk among East Asians. Applying a dominant genetic model, only in the Chinese population, the Cys allele was significantly associated with increased risk of HCC . However, two studies influenced this finding according to sensitivity analysis. Furthermore, considerable heterogeneity and bias existed among Chinese studies.Eight studies were identified involving 2369 cases and 2442 controls assessing the association of the hOGG1 Ser326Cys polymorphism is associated with HCC risk among East Asians. Well-designed and large-sized studies are required to determine this relationship.There is limited evidence to support that the  Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most frequent cause of cancer-related death worldwide hOGG1 gene, located on chromosome 3p26.2, is composed of eight exons and seven introns. Polymorphisms in this gene may alter glycosylase function and an individual’s ability to repair damaged DNA, possibly resulting in genetic instability that can foster carcinogenesis hOGG1 gene, much interest has been focused on the Ser326Cys (C>G) polymorphism (rs1052133). It is in exon 7 of the hOGG1 gene, which takes the form of a single amino acid substitution, from serine to cysteine at condon 326. Although the evidence is inconclusive that this functional polymorphic variation influences the activity of hOGG1 Human 8-hydroxyguanine glycosylase 1 (hOGG1) is a DNA glycosylase enzyme responsible for the excision of 8-oxoguanine, a mutagenic base byproduct which occurs as a result of exposure to reactive oxygen hOGG1 Ser326Cys polymorphism with HCC risk among East Asians In the past years, several studies have investigated the association of the hOGG1 and HCC  independently identified and reviewed each relevant study. Disagreements were reconciled through group discussion. When more than one record was identified for the same study population, we included the most recent publication or population including more information.hOGG1 Ser326Cys polymorphism, and consistency of genotype frequencies with Hardy-Weinberg equilibrium (HWE) in control subjects.Following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement for reporting meta-analyses of observational studies hOGG1 Ser326Cys polymorphism and HCC risk. The association was examined under three genetic models: the additive model (Cys/Cys vs. Ser/Ser), the dominant model (Ser/Cys+Cys/Cys vs. Ser/Ser) and the recessive model (Cys/Cys vs. Ser/Cys+Ser/Ser). HWE was tested using the chi-squared test and it was considered statistically significant when the P value is less than 0.05. Sensitivity analyses were carried out using the one-study remove approach to assess the impact of each study on the combined effect.We referred to a previous study to perform statistical analysis 2I statistic and a chi-square based Q test. A P value of more than 0.05 for the Q test indicated a lack of heterogeneity among the studies, so the summary OR estimate of each study was calculated by the fixed-effect model (the Mantel-Haenszel method) Heterogeneity assumption was checked by the hOGG1 Ser326Cys polymorphism and HCC susceptibility (P<0.001) There were 8 studies identified on the tibility  [9], [10et al. used two control groups  hOGG1 Ser326Cys polymorphism and HCC risk was observed under the dominant genetic model . As the hOGG1 Ser326Cys polymorphism in control subjects did not fulfill HWE in the study by Ji et al.hOGG1 Ser326Cys polymorphism and HCC risk under the dominant genetic model  Subgroup analyses were performed by dividing studies into groups according to ethnicity and source of controls. Only in the Chinese population, significant association between the PEgger’s test = 0.03; Begg’s funnel plot and Egger’s test were performed to assess the publication bias of the literatures. The results indicated that bias may exist among Chinese studies  and are closely associated with inflammatory infiltration hOGG1 Ser326Cys polymorphism and HCC risk hOGG1, these include hepatitis virus, smoking, alcohol consumption, meat intake, and other factors that are thought to induce DNA damage hOGG1 Ser326Cys polymorphism in populations exposed to some of the above factors hOGG1 Ser326Cys polymorphism on HCC risk. Fourthly, like most meta-analysis, this study is based on unadjusted estimates, while a more precise analysis might be conducted if individual data were available, which could allow for an adjusted estimate by confounding factors. At last, quality of reporting is low in most included studies, although lack of reporting should not be assumed to imply poor quality of a study Our meta-analysis has several limitations. Firstly, only 8 published studies were included, thus the meta-analysis was restricted to a relatively small population. All the 8 studies studied East Asian population, a population with high-HCC risk. So, our findings are not suitable for other populations, especially in Caucasian population which has a low-HCC risk. Recently, one study involving Caucasian population failed to find any association between the http://www.genome.gov/gwastudies/). The hOGG1 Ser326Cys polymorphism has not been highlighted in these studies.We reviewed full-text and supplementary data of GWAS studies of HCC identified in the Catalogue of Published Genome-Wide Association Studies Click here for additional data file.Methods S2Protocol for this meta-analysis.(DOCX)Click here for additional data file.Methods S3Checklist to confirm compliance with PRISMA guidelines for systematic reviews and meta-analyses.(DOCX)Click here for additional data file.


Alpha-methylacyl-CoA racemase (AMACR) is a mitochondrial and peroxisomal enzyme that is overexpressed in prostate cancer. The aim of this study was to confirm and expand the findings that the PCa risk increased in men associated with AMACR expression across various geographic regions.A systematic search of databases was carried out and other relevant articles were also identified. Then the meta-analyses were conducted according to the standard guidelines.P<0.00001). Subgroup-analysis showed that findings didn’t substantially change when only Caucasians or Asians  were considered. Expression of AMACR by PCR in relation to PCa risk suggested that AMACR was associated with PCa . There was also no significant publication bias observed.A total of 22 studies with 4,385 participants were included on the basis of inclusion criteria. AMACR by IHC was significantly associated with increased diagnosis of PCa (OR = 76.08; 95% CI, 25.53–226.68; Our findings provide further evidences that the expression of AMACR contribute to PCa risk. AMACR protein overexpression was found in prostate cancers, low expression in any of the normal tissues or in benign prostatic tissue. AMACR is potentially an important prostate tumor marker. Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy in men, and the second leading cause of male cancer-related mortality in the United States Although prostate-specific antigen (PSA) is the main criteria for PCa diagnosis, it has poor specificity to cancer, highly expressed in noncancerous prostatic tissues as well as in cancerous tissues and often lead to over diagnosis and overtreatment. Consequently a new scenario is needed to identify potentially aggressive or lethal PCa to better support clinical decisions AMACR , an enzyme currently used in prostate cancer diagnosis, which is a peroxisomal and mitochon drial enzyme that was preferentially overexpressed to approximately 80% of prostate cancer detected in prostate biopsies In an attempt to confirm the potential role of AMACR expression as a prognostic biomarker, we completed a meta-analysis of AMACR expression in men of Asia and European lineage across different geographic regions with PCa.We undertook a comprehensive literature review with search terms  without Studies were included if they fulfilled the following criteria: 1) cases were pathologically verified to have adenocarcinoma of the prostate , 2) the control group consisted of subjects who were men and free of PCa, 3) studies investigating the association of AMACR with PCa risk as the main outcome.This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Study characteristics, ethnicity of included subjects, numbers of cases and control subjects, and positive staining were extracted for factors of interest. The authors of published studies were also contacted for requesting necessary data that were not provided. Quality assessment was undertaken independently by at least two authors . Two authors  independently did the literature search and extracted data. Any disagreements were resolved through discussion with authors (Niu and Zhou).I2 statistic that represented the percentage of total variation across studies. As a guide, I2 values of 25%, 50%, and 75% correspond to low, medium, and high levels of heterogeneity The effect estimates of choice were odds radio (OR) for dichotomous variables and the corresponding 95% confidence intervals (CI). The random effects model of DerSimonian and Laird was prespecified for use in all estimates because of the suspected a priori that studies were conducted by various authors with different populations and had different designs . Heterogeneity was evaluated using the Q test The literature searches yielded a total 897 studies. After review of the abstracts, 118 studies were identified as potentially eligible for inclusion. After full review, 17 studies The included studies were published from 2004 to 2012. Five conducted in Asia, the others in western countries. Most of included studies chose benigh prostate hyperplasia. The details were listed in The pooled result revealed that positive AMACR by IHC was significantly associated with increased diagnosis of PCa  . Funnel In consideration of the potential different expression of AMACR in different races, we yielded enthnicity-based subgroup-analyses . SubgrouWe next explored the positive AMACR by PCR in relation to PCa risk. Pooled results suggested that positive AMACR was associated with PCa  . There wP<0.00001). The overall-analysis provided strong replication of the initial findings, confirming the AMACR for PCa.In this study, we explored the association between the AMACR and PCa risk in 22 studies from various geographic regions including European and Asia. AMACR expression by IHC was significantly associated with increased diagnosis of PCa -a-methyl-branched-chain fatty acyl-CoA esters to their (S)-stereoisomers. AMACR was identified as being overexpressed in prostate carcinoma cells when compared with benign or normal prostate epithelial cells Strengths of this study include its large sample size. Because of this, the geographic regions were distinguished in subgroup-analyses. However, our results are based on unadjusted estimates, some un-provided parameters known to be associated with prostate carcinogenesis, such as inherent nature, might substantially confound the presented results.Meta-analysis of the comprehensive literature revealed that the AMACR expression was strongly associated with PCa risk in man from various regions. There was no varying between Caucasian and Asian man.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.