XRCC1) Arg399Gln, Arg194Trp, Arg280His, −77T>C, and X-ray repair cross-complementing group 3 (XRCC3) T241M polymorphisms with lung cancer risk, but the results remained controversial. Hence, we performed a meta-analysis to investigate the association between lung cancer risk and XRCC1 Arg399Gln , Arg194Trp , Arg280His , −77T>C , and XRCC3 T241M  in different inheritance models. We found that −77T>C polymorphism was associated with increased lung cancer risk  when all the eligible studies were pooled into the meta-analysis. In the stratified and sensitive analyses, significantly decreased lung cancer risk was observed in overall analysis , Caucasians , and hospital-based controls  for XRCC3 T241M. In conclusion, this meta-analysis indicates that XRCC1 −77T>C shows an increased lung cancer risk and XRCC3 T241M polymorphism is associated with decreased lung cancer risk, especially in Caucasians.Many studies have reported the association of X-ray repair cross-complementing group 1 ( Lung cancer is a major cause of cancer-related death in the worldwide and the overall survival rate has still an extremely poor XRCC1 play a central role in the BER pathway XRCC1 is located on chromosome no. 19q13.2–13.3, and its gene product is implicated in single-strand break repair and base excision repair mechanisms XRCC1 encodes a protein that function in the repair of single-strand breaks. Shen et al XRCC1 gene at codons 194 (Arg to Trp), 280 (Arg to His), and 399 (Arg to Gln). 5′UTR–77T>C is a novel polymorphism identified in the XRCC1 gene located in the 5′untranslated region. Hao et al. The DNA repair pathways, including nucleotide excision repair (NER), base excision repair (BER) and double-strand break repair (DSBR) play an important role in repairing the DNA damage resulting from chemical alterations of a single base, such as methylated, oxidized, or reduced bases XRCC3 participate in DNA double-strand break/recombination repair and likely participates XRCC3 gene results in an amino acid substitution at codon 241 (Thr241Met) that may affect the enzyme function and/or its interaction with other proteins involved in DNA damage and repair In the DSBR pathway, XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and XRCC3 T241M with lung cancer risk XRCC1 Arg194Trp, Arg280His, and Arg399Gln with lung cancer risk have shown conflicting conclusions. Hence, the association of these polymorphic genes remains unknown. In order to explore the association between XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and XRCC3 T241M polymorphisms with lung cancer risk, a meta-analysis was conducted to summarize the data. Meta-analysis is a powerful tool for summarizing the different studies. It can not only overcome the problem of small size and inadequate statistical power of genetic studies of complex traits, but also provide more reliable results than a single case–control study.Molecular epidemiological studies have reported the association of XRCC1” or “XRCC3”, “polymorphism”, and “cancer” or “carcinoma” combined with “lung”. All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. We excluded data that were unpublished or published in abstract only. We also reviewed the Cochrane Library for relevant articles. Additional articles were identified by hand searching references in the eligible articles and review articles that possibly have been missed in the initial search. Authors were contacted directly regarding crucial data not reported in original articles. When the same sample was used in several publications, only the study with the largest sample size was included following careful examination.A comprehensive literature search was performed using the PubMed, ISI, and Embase databases for relevant articles published  with the following key words “XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and XRCC3 T241M polymorphisms and lung cancer risk, and (3) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI). Major reasons for exclusion of studies were as follows: (1) not cancer research, (2) only case population, (3) duplicate of previous publication, and (4) the distribution of genotypes among controls are not in Hardy–Weinberg equilibrium (P<0.01).The included studies needed to have met the following criteria: (1) only the case–control studies were considered, (2) evaluated the XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and XRCC3 T241M genotypes whenever possible. Ethnicity was categorized as “Caucasian”, “African”, and “Asian”. When a study did not state which ethnic groups were included or if it was impossible to separate participants according to phenotype, the sample was termed as “mixed population”. We did not define any minimum number of patients to include in this meta-analysis. Articles that reported different ethnic groups and different countries or locations, we considered them different study samples for each category cited above.Information was carefully extracted from all eligible studies independently by two investigators according to the inclusion criteria listed above. The following data were collected from each study: first author's name, year of publication, country of origin, ethnicity, source of controls, genotyping method, match, sample size, and numbers of cases and controls in the XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and XRCC3 T241M polymorphisms and lung cancer risk. The pooled ORs were performed for dominant model ; recessive model ; additive model , respectively. Between-study heterogeneity was assessed by calculating Q-statistic  2I value, Venice criteria 2I test included: “2I<25% represents no heterogeneity, 2I = 25–50% represents moderate heterogeneity, 2I = 50–75% represents large heterogeneity, and 2I>75% represents extreme heterogeneity”. If results were not heterogeneous, the pooled ORs were calculated by the fixed-effect model  χ2 or Fisher exact test) only in control groups, and deviation was considered when P<0.01. Begg's funnel plots Crude odds ratios (ORs) together with their corresponding 95% confidence intervals (95% CIs) were used to assess the strength of association between the XRCC1 and XRCC3. In addition, Genotype distributions in the controls of all the eligible studies were in agreement with HWE. 4 articles XRCC1 Arg399Gln (from 41 studies), 7,426 cases and 9,603 controls for Arg194Trp (from 23 studies), 6,211 cases and 6,763 controls for Arg280His (from 16 studies), 2,487 cases and 2,576 controls for −77T>C (from 5 studies), and 8,560 cases and 11,557 controls for XRCC3 T241M (from 19 studies). Among these studies, five studies were included in the dominant model only because they provided the genotypes of TM+MM versus TT or Arg/Gln+Gln/Gln versus Arg/Arg as a whole and one study was included in the recessive model only because it provided the genotypes of TM+TT versus MM. 45 were population-based studies and 59 were hospital-based studies. 51 were conducted in Caucasians, 46 were conducted in Asians, and 6 studies were conducted in Africans. The remained were conducted in mixed ethnicity. Tables S1–S5 in XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and XRCC3 T241M. All of the cases were pathologically confirmed.Relevant publications were retrieved and preliminarily screened. As shown in XRCC1 Arg399Gln polymorphism and lung cancer risk. When all the eligible studies were pooled into the meta-analysis of XRCC1 Arg399Gln polymorphism, no significant association was found in any genetic model. However, significant between-study heterogeneity was detected in any genetic model. Hence, we performed subgroup analysis by ethnicity, histological type, smoker habits, gender, and source of controls. Among the stratified analysis, significantly increased lung cancer risk was observed in non-smokers .XRCC1 Arg194Trp polymorphism and lung cancer risk. When all the eligible studies were pooled into the meta-analysis of XRCC1 Arg194Trp polymorphism, significantly increased risk of lung cancer was observed in the recessive model  and additive model . Among the stratified analyses, significantly increased lung cancer risk was observed in Asians  and the hospital-based controls .XRCC1 Arg280His polymorphism and lung cancer risk. When all the eligible studies were pooled into the meta-analysis of XRCC1 Arg280His polymorphism, no significant association was observed in any genetic model. In the stratified analyses, there was not still significant association between XRCC1 Arg280His polymorphism and lung cancer risk.XRCC1 −77T>C polymorphism and lung cancer risk. When all the eligible studies were pooled into the meta-analysis of XRCC1 −77 T>C polymorphism, significant increased risk of lung cancer was observed in any genetic model ; recessive model comparison (XRCC1 Arg399Gln: Ph = 0.017 and XRCC3 T241M = 0.003); additive model comparison (XRCC1 Arg399Gln: Ph = 0.003 and XRCC3 T241M<0.001). Then, we assessed the source of heterogeneity by meta-regression analysis. We found that source of controls, ethnicity, and sample size did not contribute to substantial heterogeneity among the meta-analysis (data not shown). Sensitivity analyses were conducted to determine whether modification of the inclusion criteria of this meta-analysis affected the results. Although the sample size for cases and controls in all eligible studies ranged from 100 to 8,488, the corresponding pooled ORs were not qualitatively altered with or without the study of small sample. However, for XRCC1 Arg399Gln polymorphism, when one study was excluded, the results were changed in non-smokers . For XRCC1 Arg194Trp polymorphism, when one study was excluded, the results were also changed in overall analysis , Asians , hospital-based studies , and smokers . For XRCC3 T241M polymorphism, when one study was excluded, significantly decreased lung cancer risk was observed in overall analysis , Caucasians , and hospital-based controls .There was significant heterogeneity among these studies for dominant model comparison , Arg194Trp , Arg280His , −77T>C , although possible publication bias was suggested between XRCC3 T241M polymorphism and lung cancer risk in dominant model (P = 0.012) and additive model (P = 0.041). This might be a limitation for this meta-analysis because studies with null findings, especially those with small sample size, are less likely to be published. The Duval and Tweedie non-parametric “trim and fill” method was used to adjust for publication bias. Meta-analysis with and without “trim and fill” did not draw different conclusion . It is well known that a number of proteins are involved in these steps, of which XRCC1 play key roles. XRCC1 acts as a facilitator or coordinator in BER, through its interaction with poly (ADP-ribose) polymerase, DNA polymerase b, and DNA ligase III XRCC1 −77T>C polymorphism is associated with increased lung cancer risk when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, significantly decreased lung cancer risk was observed in Caucasians for XRCC3 T241M, but not in Asians. It should be considered that the apparent inconsistency of these results may underlie differences in ethnicity, lifestyle and disease prevalence as well as possible limitations due to the relatively small sample size. The current knowledge of carcinogenesis indicates a multi-factorial and multistep process that involves various genetic alterations and several biological pathways. Thus, it is unlikely that risk factors of cancer work in isolation from each other. And the same polymorphisms may play different roles in cancer susceptibility, because cancer is a complicated multi-genetic disease, and different genetic backgrounds may contribute to the discrepancy. And even more importantly, the low penetrance genetic effects of single polymorphism may largely depend on interaction with other polymorphisms and/or a particular environmental exposure.Overall, our meta-analysis indicates that XRCC1 and XRCC3 polymorphisms with lung cancer risk. Kiyohara et al. XRCC1 Arg399Gln polymorphism was associated with increased lung cancer risk among Asians  and Arg194Trp and Arg280His polymorphisms were not associated with lung cancer risk. However, at any case, their results about Arg399Gln and lung cancer risk essentially remains an open field in Asians, as the number of studies (n = 6) is considerably smaller than that needed for the achievement of robust conclusions XRCC3 Thr241Met polymorphism and lung cancer risk. Zhan et al. XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and T241M polymorphisms that the data by the previous meta-analysis XRCC1 −77 T>C polymorphism, the T to C mutation greatly enhances the affinity of nuclear protein Sp1 to the XRCC1 promoter region, which may inhibit its transcription XRCC3 Thr241Met polymorphism and lung cancer risk in Asians and Africans. Hence, a case–control study with larger sample size or multiple center study will be needed to get conclusive results in Asians and Africans.Present meta-analysis results were not consistent with a previous meta-analysis XRCC1 R399Q (QQ or QR) substitution compared with that of the RR genotype, suggesting that the polymorphism was associated with resistance to oxaliplatin/5-FU therapy XRCC1 codon 194 variant was having a significant protective effect on development of late radiotherapy reactions in normal tissue XRCC1 protein expression were associated with improved cancer-specific survival in patients following radical radiotherapy. However, Liu et al. XRCC1 Arg399Gln and Arg194Trp might play important roles in the drug sensitivity during chemotherapy and radio sensitivity during radiotherapy and XRCC1 −77 T>C may be not play important roles in the drug sensitivity during chemotherapy.DNA repair is well known as a “double-edged sword” in cancer studies. Epidemiological evidence supports that DNA repair capacity is one of the determinants of genetic susceptibility to cancer XRCC3 T241M and Li et al. XRCC1 Arg280His. The reason may be that the study of Improta et al. Heterogeneity is a potential problem when interpreting the results of all meta-analyses. As looked through our study carefully, we found that the study of Improta et al. XRCC3 T241M polymorphism and lung cancer risk, adjusting for possible publication bias using the Duval and Tweedie nonparametric “trim and fill” method showed that the results did not change, indicating that the whole pooled results should be unbiased. Third, our meta-analysis explores and analyzes the sources of heterogeneity between studies about XRCC3 T241M and Arg280His in lung cancer risk.Some limitations of this meta-analysis should be addressed. First, misclassifications on disease status and genotypes may influence the results, because cases in some studies were not confirmed by pathology or other gold standard method, and the quality control of genotyping was also not well-documented in some studies. Second, in the subgroup analysis may have had insufficient statistical power to check an association, Third, our results were based on unadjusted estimates, while a more precise analysis should be conducted if individual data were available, which would allow for the adjustment by other co-variants, including environmental factors and other lifestyle. In spite of these, our meta-analysis also had some advantages. First, it provides pooled data on a substantial number of cases and controls and increased statistical power of the analysis. Second, although possible publication bias was suggested between XRCC1 −77T>C shows an increased lung cancer risk and XRCC3 T241M polymorphism is associated with decreased lung cancer risk in Caucasians. However, a study with a larger sample size is needed to further evaluate gene-environment interaction on XRCC1 Arg399Gln, Arg194Trp, Arg280His, −77T>C, and XRCC3 T241M polymorphisms and lung cancer risk.In conclusion, this meta-analysis indicates that Checklist S1PRISMA 2009 checklist.(DOC)Click here for additional data file.File S1Table S1, Genotypes, p values and subset of cases of XRCC1 Arg399Gln polymorphism included in the meta-analysis. Table S2, Genotypes, p values and subset of cases of XRCC1 Arg194Trp (rs1799782) polymorphism included in the meta-analysis. Table S3, Genotypes, P values and subset of cases of XRCC1 Arg280His (rs25489) polymorphism included in the meta-analysis. Table S4, Genotypes, P values and subset of cases of XRCC1 −77T>C (rs3213245) polymorphism included in the meta-analysis. Table S5, Genotypes, P values and subset of cases of XRCC3 T241M (rs861539) polymorphism included in the meta-analysis.(DOC)Click here for additional data file.


BRCA2 N372H is the only common polymorphism that leads to the amino acid change based on the reports up to date. Previous studies explored the relationship between the single nucleotide polymorphism and ovarian cancer risk, but the results were inconsistent or inconclusive.The BRCA2 gene and ovarian cancer susceptibility, a systematic literature search was performed for related publications in the databases of PubMed, Gene, and Google Scholar.To investigate the association between N372H in 2 -based Q test and an I2 index were used to identify the heterogeneous records. Potential publication biases were assessed by Begg and Egger tests.Total 2344 cases and 9672 controls in eligible studies were included in this meta-analysis. χBRCA2 codon 372 polymorphism and increased risk of ovarian cancer (HH versus NN: odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.01–1.48, P = 0.037). In the Australia subgroup analysis, significant association was also detected . The subgroup analysis for serous cancer subgroup showed that the significant association could be detected under recessive model  and under homozygote comparison .In the overall analysis, the results showed a significant association between Our meta-analysis suggests that the N372H polymorphism is associated with susceptibility of ovarian cancer. The allele H might increase the risk of ovarian cancer, especially, for ovarian cancers of the serous subtype. Despite the intensive studies in this field, which profoundly advanced our understanding of ovarian cancer, the exact molecular pathogenesis of epithelial ovarian serous carcinoma still remains elusive.2 And the traditional screening strategies, such as ultrasound and CA-125 level detection have not yet been shown to improve overall survival.3Ovarian cancer is the most lethal gynecologic malignancies worldwide. The vast majority of malignant ovarian cancers is of epithelial origin and can be classified into 4 major subtypes: serous, mucinous, endometrioid, and clear cell.BRCA2 involves in DNA double-strand break repair pathway. The mutations on this gene confer high susceptibility to ovarian cancer.4 Although recent studies already identified several high-risk ovarian cancer genes, common low-penetrance susceptibility alleles might still exist, which leads to moderate increase in ovarian cancer risk. Among all the single nucleotide polymorphisms, the rs144848 in exon 10 is the only polymorphism that change the amino acid (from asparagine to histidine), with an exceptional high-allele frequency.5 The transition is located at the region (residues 290–453), which has been identified to interact with the histone acetyltranferase P/CAF.614 only a few studies focused on this single nucleotide polymorphism for ovarian cancer risk, and the conclusions are inconsistent. We thus, performed this meta-analysis to derive a more precise and up-to-date estimation of the association between BRCA2 N372 and ovarian cancer risk.Compared with the many published studies on this polymorphism for breast cancer susceptibility,BRCA2 N372H polymorphism,” “rs144848,” “BRCA2 Asn372His polymorphism,” and “ovarian cancer.”Literature search was performed from the NCBI Global Cross-database, including PubMed, Gene, as well as Google Scholar with the following keywords: “BRCA2 N372H polymorphisms and ovarian cancer risk; the raw data should have sample size, odds ratio (OR) with 95% confidence interval (CI), or the relevant information should be able to be retrieved; if the studies from different articles overlap, we only keep the ones showing the most extensive results.To obtain the qualified data for this analysis, we set up the following inclusion criteria: the data should come from case-control studies; the articles should aim at investigating the association between 15 evaluation, all studies were evaluated as well-defined and eligible to be referred to in a meta-analysis . The data collection flow chart is shown in Figure After a thorough review of all articles from the literature search, total 6 case-control studies from 4 articles were included in our final meta-analysis for association between N372H polymorphisms and ovarian cancer risk. Based on the Newcastle–Ottawa ScaleOur analyses were based on previous published studies, thus, no ethical approval and patient consent are included.BRCA2 codon 372 polymorphisms in both cases and controls. Characteristics of individual studies were summarized in Table We extracted the following information from all qualified studies: first author, publication date, countries, ovarian cancer subtypes, number of cases, and controls and the frequencies of 2 test for the goodness of fit of Hardy–Weinberg Equilibrium in controls. A P-value <0.05 was considered as significant disequilibrium. The results were shown in Table BRCA2 gene polymorphism and ovarian cancer susceptibility from the extracted dataset. The heterogeneity between studies was examined by χ2-based Q test and I-squared index. When there was no significant heterogeneity , the pooled OR was estimated by Mantel–Haenszel fixed-effect model.16 Otherwise the D-L random-effect model 17 was applied. The risk of dominant model (NH + HH versus NN), recessive model (HH versus NH + NN), and homozygote model (HH versus NN) of BRCA2 gene polymorphism for the entire dataset were evaluated, respectively with ORs and 95% CIs. Subgroup analysis based on ethnic  or different cancer subtypes (serous ovarian cancer versus nonserous ovarian cancer) were carried out similarly. Meta-analysis was performed by STATA (version 12.0). Publication bias was assessed by Begg funnel plot and Egger linear regression test. The asymmetric funnel plot is an indication of possible publication bias.The genotype data were subjected to asymptotic Pearson χ21 Detailed exclusion criteria were shown in Figure BRCA2 N372H polymorphism and human ovarian cancer risk. The Hardy–Weinberg Equilibrium for all 4 publications was calculated. One of the 2 datasets from Beesley study (b) was excluded from the final analysis because of the statistically significant deviation from HWE . No significant violation of HWE  was detected for other 5 studies including Auranen (a), Auranen (b), Beesley (a), Wenham and Dombernowdky. The characteristics of all studies with 2344 cases and 9672 controls were summarized in Table A total of 4 articles (including 6 studies) from 248 publications were included in present meta-analysis.BRCA2 N372H polymorphism and increased risk of ovarian cancer in the homozygote model (HH versus NN) with OR 1.22  (Table P = 0.134) and recessive model (HH versus NN + NH) with OR 1.20   (Table P = 0.032)   with OR 1.40  Table  C and reBRCA2 N372H polymorphism has marginally elevated risk in the dominant model with the overall OR 1.18 . Statically significant association could be detected under recessive model  and under homozygote comparison  (Table P = 0.848). For recessive model, the overall OR was 1.11  and for homozygote comparison, the overall OR was 1.09  ,23 the progesterone receptor,24 p53 27, and RAD52.28 In our study, we investigated the association of BRCA2 gene N372H polymorphism with ovarian cancer risk in the context of a case-control study. The majority of ovarian cancers are sporadic; only approximately 10% cases are hereditary. Although mutations on BRCA2 is one of the major cause of hereditary ovarian cancers, the expression profiles are also altered in sporadic ovarian cancers, which are known as the “BRCAness”of sporadic cancers. Therefore, it is logical to seek low-penetrance susceptibility alleles in this gene. Among all the BRCA2 gene SNPs reported up-to-date, N372H (rs144848) is the most common polymorphism that leads to an amino acid change, where the basic N residue is substituted by the structurally smaller neutral residue H. Although the exact function of this nonconservative substitution is still unknown, it might alter the protein structure and function, as it is located at the N-terminal region where BRCA2 interacts with P/CAF to activate other gene transcription.Several genes polymorphisms in ovarian cancer risk have been explored, such as Vitamin D receptor FokI,P = 0.03) based on 1121 ovarian cancer cases and 2643 controls from British, and Australian studies. Although Wenham et al (2003) concluded that no such association could be detected in their study from 312 cases and 401 controls in North Carolina. In the present meta-analysis, we did not find a statistically significant association under the homozygous model (HH versus NN) for either overall or Australia subgroup data from pooled 3147 cases and 10,497 controls. From the combined analysis of all 5 studies, the genotypes (NH + HH), however, were determined to have a 1.12× increased risk  for ovarian cancer compared with 372NN genotype. For the Australia subgroup analysis, we also detected a significant association between N372H polymorphism and ovarian cancer risk under the dominant model (NH + HH versus NN) with OR = 1.17 . These results suggested that the allele H at BRAC2 codon 372 has a moderate yet definite genetic effect. The genotypes NH and HH carriers have an increased risk of ovarian cancer.Previous studies related to N372H polymorphism and ovarian cancer risk were either based on relative smaller sample size, different ethnic group, or different methodologies. The conclusions were somehow inconsistent or inconclusive. For example, Auranen et al (2003) found that the HH genotype was associated with an increased risk of ovarian cancer with OR 1.36 . This is in agreement with other previous studies, as they also suggested the HH homozygotes may be at greater risk in serous ovarian cancers.18The present meta-analysis also indicated that there exists a much stronger association between 2-based Q test and I squared test. The P-values were >0.1 and I2 were <50% for all the analysis performed in our study, indicating that no significant heterogeneity was detected; Publication bias—in our study, potential publication bias was visualized by the funnel plot and was further evaluated by Egger test. The P-values of Egger test are greater than 0.5 under all models for overall datasets, which provided evidence for the symmetry of funnel plots in our meta-analysis. We cannot, however, exclude the possibility of publication bias for Australia subgroup dataset, as only 3 publications were included in this subgroup. Caution should be taken when interpreting the results in this subgroup. More data are required to generalize our results in other ethnicities. HWE test in the control group showed that the distribution of genotypes in 1 of the 2 datasets from Beesley study is not in HWE, possibly because of systematic errors in genotyping or others. As for the retrospective study, meta-analysis is subject to methodological limitations, which emphasizes the need to interpret our results with caution.Meanwhile, some limitations might be present in our analysis: The heterogeneity between studies—we examined the heterogeneity in present analysis by χIn conclusion, our meta-analysis suggests that the N372H polymorphism is associated with susceptibility of ovarian cancer. The allele H has a moderate yet definite genetic effect. The risk may be even greater for ovarian cancers of the serous subtype.


The null genotype of GSTM1 have been implicated in gastric cancer risk, but numerous individual studies showed mixed, or even conflicting results. Thus, a meta-analysis was performed.2 : 49.9%, PQ <0.001). From stratification analyses for ethnicity, alcohol drinking, Helicobacter pylori infection, an effect modification of gastric cancer risk was found in the subgroups of ethnicity, smoking status, Helicobacter pylori infection, whereas null result was found in the subgroups of alcohol drinking. We also undertook gene-gene interaction analysis between GSTM1 and GSTT1 genes for gastric cancer risk, and the results indicated that the dual null genotypes of GSTM1 and GSTT1 might elevate the risk of gastric cancer .We identified 54 individual studies involving 9,322 cases and 15,118 controls through computer-based searches of PubMed, Embase, and Cochrane Library. It was found that the null genotype of GSTM1 was associated with an increased gastric cancer risk , under the random-effects model (IThis meta-analysis suggests that the null genotype of GSTM1 may be a important genetic risk factor for gastric cancer development. Helicobacter pylori infection [The incidence and mortality of gastric cancer (GC) has been substantially falling over the last few decades in most parts of the world , howevernfection -5. In adnfection ,7.Alpha, Mu, Pi, Theta [Mu class and the Theta class of GSTs, respectively. The GSTM1 gene is located on chromosome 1p13.3 and contains 10 exons, and the GSTT1 gene is mapped to chromosome 22q11.23 and contains six exons. The common variants of GSTM1 and GSTT1 genes is the homozygous deletion (null genotype), which has been reported to causes the loss of enzymic activity and might higher the risk of various cancers. A recent meta-analysis [Helicobacter pylori infection,GSTT1 polymorphism and gastric cancer risk is of great interest, even though not often investigated.Glutathione-s-transferases (GSTs) are one of the most important supergene family of phase II isoenzymes known to catalyze the detoxification of reactive electrophilic compounds, such as carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress, chiefly by conjugation with soluble glutathione . In addii, Theta . GSTM1 aanalysis . Since Sanalysis -65. One Helicobacter pylori infection to explore the possible effects of the interactions between GSTM1 genotype and above environmental risk factors, and gene–gene interaction analysis between GSTM1 and GSTT1 genotype with respect to gastric cancer risk.To obtain more precise estimate for the association between GSTM1 polymorphism and gastric cancer risk, we conducted a quantitative meta-analysis of all available studies published until August 15, 2014. In addition, we performed subgroup analysis stratified by smoking status, alcohol drinking and We conducted a comprehensive database searching for PubMed, Embase, and Cochrane Library through August 15, 2014 for relevant studies that estimated the association between GSTM1 polymorphism and risk of gastric cancer using the following search terms: (1) gastric cancer, gastric carcinoma, gastric adenocarcinoma, stomach neoplasm, stomach cancer, GC; (2) Glutathione-s-transferases, GSTs, GST mu, GSTM, GSTM1, GST1; (3) polymorphism, SNP, variant, mutation, genetic polymorphism. The scope of the computerized literature search was also expanded on the basis of the reference lists of eligible articles. There was no restriction on language.We first performed an initial screening of titles or abstracts to find potentially appropriate articles. A second screening was based on full-text review to identify those containing useful data on the topic of interest for inclusion in the meta-analysis. Studies were considered eligible if they met the following criteria: (1) publications assessed the relationship between GSTM1 status and gastric cancer; (2) used a cohort or case–control studies design; (3) had an appropriate description of GSTM1 status in cases and controls; (4) repored an odds ratio (OR) with 95% confidence interval (CI) or other available data for calculating OR (95% CI). Furthermore, when data from a single unique study population was republished by the same author or written in English, only the most recent article or largest report was considered. When a study reported the results on different subpopulations, we treated them as separate studies in the meta-analysis.Helicobacter pylori infection or GSTT1 genetic polymorphism in cases and controls, GSTM1 status in cases and controls. If there were any discrepancy between these two investigators, a discussion would be carried out to make an ultimate decision through the third investigator (S Li).Each article was extracted by two independent researchers (X Lao and Q Peng), who are blinded with respect to the authors, institutions and journals, using a structured sheet and entering into a database. The following data were extracted: first author, year of publication, country, ethnicity of study populations , number of cases and controls, gastric cancer diagnosis method, source of control selection, matching criteria between cases and controls, genotyping method, exposures of smoking, alcohol consumption, The strength of the association between the GSTM1 polymorphism and gastric cancer risk was measured by the odds ratio (OR) with 95% confidence interval (CI). The significance of the pooled OR was determined by Z test and a P value of less than 0.05 was considered significant. Then, we examined the associations between null genotype of GSTM1 and gasreic cancer risk on the genetic comparison model (null genotype vs. present genotype).2 statistic was calculated to assess the between-study heterogeneity, and heterogeneity was deemed as apparent when the I2 statistic value was greater than 50%. Furthermore, several subgroup meta-analyses were performed in an attempt to assessed the association between the GSTM1 null genotype and gastric cancer risk based on the ethnicity, smoking status, alcohol drinking and Helicobacter pylori infection. For these purposes, we stratified subjects (both GSTM1 present and null genotypes) according to ethnicity , smoking status (non/ever smokers); alcohol drinking (non/ever drinkers); Helicobacter pylori infection (negative/positive infection). In order to evaluate the presence of a biological interaction between GSTM1 and GSTT1 polymorphisms, additional gene–gene interaction analysis were performed by using the individuals with present genotypes for both genes as reference groups, as suggested by Botto and Khoury [In carrying out the meta-analysis, two models for dichotomous outcomes were conducted: the random-effects model and the fixed-effects model. The random-effects model, using the DerSimonian-Laird method , was cond Khoury .To validate the credibility of outcomes in this meta-analysis, a sensitivity analysis was performed by sequential omission of individual studies. Publication bias was investigated using a funnel plot, in which the standard error of logor of each study was plotted against its logor. An asymmetric plot suggested the existence of possible publication bias. In addition, funnel-plot asymmetry was formally assessed by the method of Egger’s linear regression test . If publHelicobacter pylori infection. 15 studies investigated the gene-gene interaction between GSTM1 and GSTT1 polymorphisms in the association with gastric cancer risk. Table After comprehensive searching, a total of 202 articles were retrieved, but only 49 full-text publications -27,29-65Table 2 : 49.9%, PQ < 0.001) , using the random-effects model , but not for Helicobacter pylori negative subgroup .The data were also stratified, in accordance with the smoking status, into non-smokers and ever-smokers subgroups. Statistically significant findings between the null genotype of GSTM1 and gastric cancer risk was found in both non-smokers  and ever-smokers subgroups , respectively. The data were additionally stratified, in line with alcohol driking, into the subgroup of non-drinkers and ever-drinkers. However, null results were noted in both non-drinkers  and ever-drinkers . The data were further stratified, in the light of Table A sensitivity analysis was performed by the sequential omission of individual studies. The significance of the pooled OR in both the overall analysis and subgroup analysis were not influenced excessively by omitting any single study (data were not shown).Begg’s funnel plot and Egger’s test were performed to access the publication bias of literatures. As shown in Figure Helicobacter pylori infection status did not modify the association between GSTM1 null genotype and gastric cancer risk. However, these previous meta-analysis did not cover all eligible studies published in Pubmed and even contain the overlapped data, which made their conclusions doubtable. What’s more, 12 new case–control studies [The present and null genotype of GSTM1 is one of the most widely studied metabolic gene polymorphisms as susceptibility factor for gastric cancer. In 2005, La Torre et al.  firstly  studies -65 have Helicobacter pylori infection, lifestyle, diet, or other environmental risk factors for which ethnic groups vary, may be responsible for the different associations observed in this meta-analysis.Large ethnic differences for the frequency of homozygous deletion in GSTM1 have been observed. Frequencies of homozygous GSTM1 null genotype in Japanese, Chinese, Indians (Asia), Caucasians and Africans were 48%-51%, 35%-63%, 33%-36%, 50%, 22%-35%, respectively . For theIn our meta-analysis, we proceeded the subgroup meta-analysis of pooling data from the cases and the controls on smoking status, and the suggestion of an increase risk of gastric cancer was found in not only non-smokers but also ever-smokers. Interestingly, both the OR and the upper and lower limits of corresponding 95% CI in ever-smokers are much higher than non-smokers. Smoking is an important established risk factor for gastric cancer that accouts for about 50 % increase in gastric cancer risk . JarebinFurthermore, we carried out the subgroup analysis on alcohol drinking to detect the possible effect of GSTM1 deficiency on gastric cancer risk. Alcohol drinking is supposed to be a risk factor of gastric cancer, due to the reactive oxygen species (ROSs). ROSs are produced during alcohol metabolism as a result of the generation of NADH from the conversion of ethanol to acetaldehyde by alcohol dehydrogenase, and may induce gastric mucosal oxidative injury ,80. DespHelicobacter pylori infection and the risk of gastric cancer. Helicobacter pylori is a spiral Gram-negative bacterium that colonizes the stomach, and which has been implicated as a Class 1 human carcinogen for gastric cancer [Helicobacter pylori infection was shown to eveluate the risk of gastric cancer from 2.8-to 6-fold [Helicobacter pylori related [Helicobacter pylori infection and gastric cancer. Ng EK et al. found that GSTM1 null genotype was more prevalent in gastric cancer cases with Helicobacter pylori infection than without the infection, and the result suggested that the absence of GST-mu function might have enhanced the susceptibility of these patients to the carcinogenic process initiated or facilitated by Helicobacter pylori [Helicobacter pylori infection and GSTM1 polymorphism for the risk of gastric cancer, and some risk excess was observed among Helicobacter pylori infection positive individuals compared with negative individuals by combining the data available from these six studies. However, these results should be interpreted with caution as the subset analysis involved a small number of patients and controls that may have affected the statistical analysis.We also examined the association between c cancer . The proo 6-fold ,85. Ther related . Howeverr pylori . In our If genetic susceptibility to gastric cancer is, in part, mediated through metabolic gene polymorphisms, it is possible that the combinations of certain genotypes may be more discriminating as risk factors for gastric cancer than a single locus genotype. Because GSTM1 and GSTT1 are involved in the detoxification of a variety of compounds, and their substrates often overlap, it is possible that individuals with a more defective genotype of these genes can be expected to at higher risk of cancers. A previous study has looked at the combination between GSTM1 and GSTT1 in gastric cancer and showed that a 95% significant increased risk of gastric cancer appeared for individuals with combined deletion mutations in GSTT1 and GSTM1 genes in comparison with individuals with both homozygous wild genotypes . Hence, Helicobacter pylori infection, as well as GSTT1 null genotype were performed by collecting data from a minority of included studies, so selection bias may have occurred in this meta-analysis. What’s more, more subgroup analyses performed on age, gender, histological types, and other factors  would be better to investigate possible biases; however, we could not perform subgroup analyses on these factors owing to the limited available information in the primary literatur.Several limitations of the study have to be acknowledged in interpreting the results. Firstly, the sample sizes for a majority of included studies were relatively small; source of controls were somewhat different from each other; the matching criteria for the cases and controls were also not strict. Thus, robust guarantee could hardly be made among all those eligible studies. Additionally, only published studies were included in our meta-analysis and a publication bias have occurred. Even though non-parametric “trim and fill” method was used to adjust for it and the result suggested that meta-analysis with and without “trim and fill” method did not draw different conclusion, if the unpublished studies are not included an overestimation of the GSTM1 null effect may inevitably appear. Finally, the subgroup meta-analyses considering interactions between GSTM1 null genotype and smoking status, alcohol drinking and Helicobacter pylori-related carcinogenesis of gastric cancer, and that the combination of unfavourable GSTT1 polymorphism may result in an additional risk of gastric cancer. Future studies with large and carefully design are warranted to better understand such a association between GSTM1 null genotype and gastric cancer risk.This meta-analysis suggests that the null genotype of GSTM1 are associated with increased gastric cancer risk, and the subgroup meta-analysis on the basis of ethnicity showed that significant associations are found for Asians and Caucasians, but not for Negroids. In additon, the null genotype of GSTM1 may modulate the smoking-related and


Having the ability to scan the entire country for potential “hotspots” with increased risk of developing chronic diseases due to various environmental, demographic, and genetic susceptibility factors may inform risk management decisions and enable better environmental public health policies.Develop an approach for community-level risk screening focused on identifying potential genetic susceptibility hotpots.Our approach combines analyses of phenotype-genotype data, genetic prevalence of single nucleotide polymorphisms, and census/geographic information to estimate census tract-level population attributable risks among various ethnicities and total population for the state of California.We estimate that the rs13266634 single nucleotide polymorphism, a type 2 diabetes susceptibility genotype, has a genetic prevalence of 56.3%, 47.4% and 37.0% in Mexican Mestizo, Caucasian, and Asian populations. Looking at the top quintile for total population attributable risk, 16 California counties have greater than 25% of their population living in hotspots of genetic susceptibility for developing type 2 diabetes due to this single genotypic susceptibility factor.This study identified counties in California where large portions of the population may bear additional type 2 diabetes risk due to increased genetic prevalence of a susceptibility genotype. This type of screening can easily be extended to include information on environmental contaminants of interest and other related diseases, and potentially enables the rapid identification of potential environmental justice communities. Other potential uses of this approach include problem formulation in support of risk assessments, land use planning, and prioritization of site cleanup and remediation actions. Communities and public health agencies, such as the US Environmental Protection Agency (EPA), would benefit from being able to quickly screen local communities, and potentially the entire country, for possible geographic “hotspots” for increased risk of developing chronic diseases due to varied socioeconomic, demographic, genetic, and environmental factors. Leveraging data science approaches  should allow for the identification of these geographic areas whose populations are at increased risk due to multiple risk factors.p,p’-DDE) [Emerging evidence suggests that race, socioeconomic factors, and where one lives may adversely impact one’s risk of developing type 2 diabetes mellitus (T2DM) ,2. Recen,p’-DDE) . However,p’-DDE) . Identif,p’-DDE) , it is pWe performed literature and database searches to identify several genotypes that have been shown to be associated with T2DM . As a pip is the reported risk allele frequency, and n is the case and control study populations. Study specific frequencies of the CC genotype were calculated by summing the number of case and control carriers of the CC genotype and dividing by the total study population. Weighted CC genotype frequencies for Asian or European populations were then calculated using individual study sizes for the weights. In order to characterize the genetic risk the rs13266634 polymorphism confers to homozygous carriers, the population attributable risk (PAR) for each ethnicity was calculated as follows [E is the frequency of the CC genotype  and OR is the reported odds ratio for developing T2DM in the study populations. The PAR is the proportion of T2DM cases in the various populations expected to occur solely due to the presence of the CC risk genotype. Pooled odds ratios and 95% confidence limits were calculated from individual studies as described previously [2-based Q test. Evidence of statistical heterogeneity was assumed if the p-value for the Q test was < 0.10, or the I2 value was > 50%. If evidence of heterogeneity was evident, a random-effects model was then used. The CC frequency and PAR for a single Mexican Mestizo population was calculated using information published in the available literature [Individual studies reporting increased odds of T2DM in Asian or European carriers of the rs13266634 polymorphism were identified from a previously published 2011 meta-analysis . For thi follows :PAR=100eviously . Assuminterature . All staThe following demographic data for California on the census tract level were extracted from the 2007–2011 American Communities Survey: Caucasian population, Asian population, and Mexican (of any race) population . Total pOf the studies previously identified , 22 studInitial prevalence information was obtained from the dbSNP database, which contains the HapMap data. The rs13266634 SNP has an estimated risk allele frequency in the Mexican population of 81% (CC/CT). In the Caucasian and Asian populations, the risk allele has an estimated prevalence of 73.6% and 55.6%, respectively. For the studies used in the pooled cohort OR and PAR calculations, average risk allele frequencies in T2DM cases for Caucasians (70.4%) and Asians (61.7%) were similar to those reported in the dbSNP database; the risk allele frequency in the Mexican Mestizo population included in this analysis  also was2 = 0, p = 0.46; Caucasians: I2 = 10.4, p = 0.35). Using a random-effects model to calculate the pooled ORs resulted in similar results for both Asian and Caucasian cohorts (results not shown). Using reported data [When calculating pooled ORs for the Asian and Caucasian cohorts included in subsequent PAR calculations, homozygous carriers of the CC genotype were observed to have a statistically significant increase in the odds of having T2DM compared to those with the CT or TT genotype: OR = 1.19, 95% CI: 1.06–1.33, p < 0.01; OR = 1.21, 95% CI: 1.13–1.30, p < 0.001, respectively. Results for the Asian cohorts were similar when all cohorts were used above  or when ted data , homozygThe genetic prevalence data and pooled ORs were used to calculate PAR values for the individual ethnic groups . MexicanAs decisions regarding remediation and/or intervention strategies may be more likely made on larger geographic units than census tracts, counties that contained census tracts in the highest total PAR quintile (Q5 census tract) were identified . In totaThe current analysis presents a predictive risk screening approach to identifying census tract locations of communities potentially at risk of developing chronic diseases due to genetic susceptibility factors. Through the mining of genome-wide association study databases, we were able to identify genes encoding proteins that rely upon metals for their catalytic activity, and their relationship to T2DM. A similar approach has been used previously: an environment-wide association study (EWAS) using survey-weighted logistic regression was conducted on the NHANES data from 1999–2006 to identify chemical exposures and nutrients that may be associated with T2DM . They foWe used prevalence information about the SLC30A8 gene polymorphism rs13266634 to perform a geographic and demographic-based predictive screening pilot focused on the State of California. In this pilot we identified census tracts with elevated PAR for developing T2DM based on the prevalence of rs13266634 in various human populations. Census tracts with a higher PAR will likely contain individuals who may respond more poorly to chemical exposures.While this study highlights a method for incorporating information on markers of genetic susceptibility with data on the spatial distribution of potentially susceptible populations, there are important limitations that warrant discussion. This analysis used multiple studies ,16,24–41Although the current analysis independently calculated pooled ORs from the Asian and European cohorts, African cohorts were not included as the reported association between the C/T polymorphism and T2DM was not statistically significant in a pooled analysis  . As a reIn future analyses, the African-American population could be incorporated in one of three ways. The first method would be to simply incorporate elevated ORs for African cohorts  ignoring statistical significance. A second approach would be to acknowledge that the increase in the pooled African OR is not statistically significant, and to include the African-American population numbers in the denominator when calculating the population-weighted total PAR . This woAnother limitation in the current analysis is how ethnicity-specific information has been incorporated. First, smaller ethnic groups have been aggregated into larger sets for the purpose of calculating the PAR. For example, study populations that have been described as Asian in this analysis are made up of Han Chinese, Korean, Japanese, and Asian Indian populations. Grouping different, distinct ethnic groups, each with their individual risks, allele frequencies, and spatial distributions, most likely masks true patterns in genetic susceptibility. Disaggregated information is available on these populations on the census tract level from the Census Bureau, and could be incorporated in future analyses. However, consideration of the smaller ethnic groupings may result in issues discussed above, namely findings of non-statistically significant risks for some smaller ethnic groups. Another assumption of this analysis is that the PAR calculated from the Asian, European, and Mexican Mestizos cohorts are representative of Asian, Caucasian, and Mexican-American populations in the United States. This may be true for populations of recent immigrants, but established ethnic populations could be sufficiently different such that the PARs calculated are not representative of the true risk for multiple reasons, especially differing risk allele frequencies. In order to minimize the uncertainty in whether this assumption is true, studies investigating the risk in these populations actually living in the United States would need to be identified and incorporated into the analysis. Lastly, race and Hispanic origin are considered separate concepts by the Census Bureau, and data regarding these self-reported identities are collected independently . In the http://www2.epa.gov/toxics-release-inventory-tri-program) or National Priorities List (http://www.epa.gov/superfund/sites/npl/), and compare the clustering of high levels of contamination with the spatial patterns of total PAR distribution. Other sources of vulnerability to disease  could be incorporated into future analysis using currently available tools such as the CDC’s Social Vulnerability Index (www.svi.cdc.gov). Publically available information on T2DM prevalence is most likely only available on the county level. This discrepancy in spatial resolution between T2DM data and contaminant and PAR data would be a challenge in determining if census tracts with increased genetic susceptibility and environmental contamination also are observed to have increased T2DM rates.A natural extension of the current study is to investigate whether spatial patterns of T2DM risk due to genetic susceptibility correlate with spatial patterns of environmental pollutants, other determinants of disease, and T2DM prevalence. Future studies could locate spatially-resolved data on contamination from sources such as EPA’s Toxic Release Inventory Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig(PDF)Click here for additional data file.S4 FigTotal PAR is the subgroup population-weighted average PAR for the total population in each census tract Click here for additional data file.


PLCE1 rs2274223 polymorphism and cancer risk, but the conclusions are inconclusive. To obtain a comprehensive conclusion, we performed a meta-analysis of 22 studies with 13188 cases and 14666 controls. The pooled results indicated that PLCE1 rs2274223 A > G polymorphism was associated with an increased risk of overall cancer . The stratification analysis showed the polymorphism was significantly associated with an increased risk of esophageal squamous cell carcinoma (ESCC) other than gastric cancer (GC), especially among the subgroups of Asian, high quality score, sample size > 1000 and the studies consistent with Hardy-Weinberg equilibrium (HWE). This meta-analysis demonstrated that PLCE1 rs2274223 A > G polymorphism may be associated with increased susceptibility to cancer, especially for ESCC. However, due to the substantial heterogeneities across the studies, the conclusion might be not conclusive that need more studies to confirm.Phospholipase C epsilon 1 (PLCE1) plays an important role in cell growth, differentiation and oncogenesis. An increasing number of individual studies have investigated the association between  Cancer is a worldwide problem and its incidence is increasing year by year, which severely endangers the human health and lives. In 2008, the world has more than 12 million new cases of cancer and by 2030, this figure will be over 25 million1PLCE1 gene at chromosome 10q23 had a genome-wide significantly correlation with gastric cardia cancer (GCA) and ESCCPLCE1 and C20orf54, were associated with risk of ESCC and GCA for Chinese subjects in another large-scale GWASPLCE1 rs2274223 that has also been found in the former two GWASsAs genome-wide association studies (GWASs) strategy is putting forward, gene mutations or susceptibility loci have been identified for many diseases. To date, more than 50 GWASs focused on cancer have been published, comprising at least 15 different kinds of malignant tumorsPLCE1 gene, is a non-synonymous SNP that can cause the amino acid change from histidine to argininePLCE1 became one of the most studied polymorphic loci. A growing number of studies have been conducted to verify its association with kinds of cancer risk. However, the findings were inconsistent. The discrepancies among these studies might attribute to the relatively small sample size in each research and ethnic variation. Therefore, we performed a meta-analysis of all eligible case-control studies to systematically estimate the effects of PLCE1 rs2274223 A > G polymorphism on the susceptibility to cancer.Rs2274223, located in the 26th exon of the A total of 17 eligible articles were identified in the final meta-analysis, which contained 22 studies and involved 13188 cases and 14666 controls. The study selection process was shown in Figure 1891011121314151617181920212223Among the 22 studies, six studies reported on GC with 6813 cases and 5666 controls, and nine studies reported on ESCC with 3348 cases and 5309 controls. In the rest of the studies, there were two studies on esophageal adenocarcinoma (EAC), two studies on colorectal cancer, one study on head and neck cancer (HNC), one study on squamous cell carcinoma of head and neck (SCCHN) and one study on gallbladder cancer (GBC). All studies follow the Hardy-Weinberg equilibrium (HWE) except three studies which derived from Palmer's articlePLCE1 rs2274223 polymorphism with the risk of different types of cancer were shown in The associations of In GC, stratification analysis by genotyping methods showed that rs2274223 was significantly associated with the risk of GC using TaqMan . No significant association was detected in the subgroup analysis by ethnicity, source of control, sample size and HWE in controls .PLCE1 rs2274223 polymorphism and ESCC risk in the studies consistent with HWE  , but not for Caucasians and other ethnicities. In the stratified analysis by source of control, significant association was only found for hospital-based controls . When stratified by sample size, we observed a significantly increased risk of ESCC in large sample size whose number was more than 1000 . We also performed stratification analysis by quality score, significant association was only identified in high score . Furthermore, in the stratified analysis by HWE in controls, we found a significant increased association between 10–1.83) .P = 0.000; GA vs. AA: P = 0.000; GG/GA vs. AA: P = 0.000; GG vs. GA/AA: and G vs. A: P = 0.001)  . The met= 0.001) . We furt= 0.001) .P = 0.846; GG vs. AA: t = −0.55, P = 0.586; GA vs. AA: t = 0.22, P = 0.831; GG/GA vs. AA: t = −0.02, P = 0.983 and GG vs. GA/AA: t = −0.56, P = 0.580, which further provided no evidence of publication bias . PLCE1 protein, like other PLC families, is composed of the PLC catalytic domain, PH domain, EF domain and C2 domain. In addition, PLCE1 protein also has unique regions, two RA domains at its C terminus and a CDC25-like domain at its N terminus. Especially, the former directly interact with several Ras family GTPases, such as oncogenic KRas and HRas. Therefore, PLCE1, as a multifunctional signaling protein, plays an important role in cell growth, differentiation and oncogenesis2526PLCE1 rs2274223 polymorphism on the susceptibility of different cancer.The PLCE1 mutation is closely associated with many diseases, such as nephrotic syndromePLCE1 rs2274223 polymorphism is associated with a high risk of cancers, the exact mechanism is still unknown. Some studies suggest that PLCE1 protein plays a crucial role in the process of information transmission between the cell membrane and the nucleus. And it probably through augmenting angiogenesis and inflammation, two distinct mechanisms, acts on intestinal tumorigenesis30To our knowledge, PLCE1 rs2274223 and different kinds of cancer. Both of them demonstrated that the polymorphism increased the risk of cancer in the pooling analysis, which was the same with ours. In the stratification analysis, the former publicationPLCE1 rs2274223 polymorphism contributed to the high risk of esophageal and gastric cancer in Asians. However, in the present study, we observed an increased association in Asian ethnicity only for ESCC other than GC. The discrepancy may result from three reasons as the follows: First of all, we classified esophageal cancer into ESCC and EAC for the reason that genetic variation may have different effect on different pathological type of cancer. Because of a limited number of published studies for EAC, we failed to perform further stratification analysis. Therefore, the association between the PLCE1 rs2274223 polymorphism and EAC risk was ambiguous. Secondly, the positive result about GC might be attributed to small sample size, when we increased the number more than half, we failed to find the significant association. Moreover, the former study mistakenly put the northern Indian population into Asians which may make the result bias. The latter studyPLCE1 rs2274223 polymorphism was associated with the risk of upper aerodigestive tract cancer  but not with gastric and colorectal cancer. However, we did not combine the HNC, SCCHN, EAC and colorectal cancer, because it might be more appropriate to show the results without meta-analysis when the number of studies was less than three.Two previously meta-analyses33Compared with the previous publications, our meta-analysis has advantages. Above all, this is by far an analysis with the largest sample size which provided a power of above of 80% investigating the association. What is more, among all the included studies, 95.45% (21/22) were considered as high quality. Furthermore, sensitivity analysis revealed no significant influence of a single study on the summary ORs or the 95% CI. Additionally, no obvious evidence of publication bias existed, which indicated that the result may be unbiased. Some studies have discovered some sequence variants in the region of chromosome, such as 5p15.33 and 8q24, are associated with risk of different cancer types35363738There was substantial between-study heterogeneity in the meta-analysis. So, although the statistical evidence proved the findings to be reliable, we did not deem lightly of the issue. We used random-effects model to incorporate heterogeneity among studies. However, random-effects model is not a substitute for a thorough investigation of heterogeneity. In addition, we performed the analysis with strict criteria for study inclusion, carried out meta-regression but found no source of heterogeneities. However, further stratification analysis demonstrated that cancer type, source of control and sample size may be the main source of heterogeneities. Besides, there is other heterogeneity that cannot be explained.Some other limitations should be acknowledged. Firstly, although we had enrolled 22 studies, the sample size for certain cancer types and ethnicities remained relatively small that we could not perform further subgroup analyses. Secondly, we failed to conduct the adjusted estimates for unavailable original data, such as age, sex, smoking and drinking status et al which could make the result masked. Thirdly, some studies are hospital-based design which would not represent the people who live in a certain region. Lastly, even though there is no statistical evidence of publication bias, we may miss some unpublished investigations showing no significant effect or publications written in other languages. Additionally, the power of the funnel plot to test the asymmetry is relatively low when studies were less than 30 or smaller studies were lower methodological quality. What is more, most of the data are retrospective in the meta-analysis. Therefore, reporting publication bias from prospective studies is needed.PLCE1 rs2274223 polymorphism may be associated with increased susceptibility to cancer, especially for ESCC. However, due to the limitations of the meta-analysis, the conclusion might be not conclusive which need more studies with larger sample size and appropriate design to confirm.In conclusion, the meta-analysis suggests that We identified publications from PubMed and The New England Journal of Medicine (OVID platform) using the following search items: “PLCE1” or “Phospholipase C epsilon 1” “SNP” or “polymorphism” or "variant", and “cancer” or "carcinoma" or "neoplasm" or "malignance". We also identified related publications written in Chinese from China National Knowledge Infrastructure (CNKI) and WanFang database using the combinations terms of “PLCE1” or “Phospholipase C epsilon 1” “SNP” or “polymorphism” or "variant", and “cancer” or "carcinoma" in Chinese. The languages were limited to English and Chinese. We further screened the whole references with the date up to April 2014 and confirmed potential relevant studies according to the title and abstract.PLCE1 rs2274223 polymorphism and cancer susceptibility; (c). Case-control studies; (d). Genotype data available. In addition, exclusion criteria were as follows: (a). Overlapped articles or repeated studies; (b). Review articles, dissertations and conference reports.All studies included in the meta-analysis are accorded with the following inclusion criteria: (a). Full text available; (b). Study focus on the association of Two researchers independently extracted data from each eligible study with the following items: the first author, year of publication, the type of cancer, country, ethnicity, source of controls, genotyping technology, number of cases and controls, the quantity of each genotype in cases and controls, Minor Allele Frequency (MAF) and value of HWE. In order to ensure the accuracy of the data, when encountering inconsistent, we discussed together to reach a consensus.According to the quality assessment criteria , we assePLCE1 rs2274223 polymorphism and the risk of cancer was evaluated by the pooled odds ratios (OR) and 95% confidence interval (CI). If the P value of the Z test was less than 0.05, we considered the pooled OR statistically significant. Heterogeneity was analyzed using the Chi-squared-based Q-test. When there existed significant heterogeneity (P < 0.10), the random-effects model was usedP < 0.05 was considered significant)43STATA software  was used to perform all analyses. We used allelic (G vs. A), homozygote (GG vs. AA), heterozygote (GA vs. AA), dominant (GG/GA vs. AA) and recessive (GG vs. GA/AA) as the models. The genetic association between the L.Z.L. and J.H. conceived and designed this study; Y.W.W., M.L.Z. and W.J.X. searched databases and collected the data; W.J.X. and M.L.Z. performed the statistical analysis, interpretation of data and wrote the manuscript. All authors reviewed the final manuscript.Supplementary information


Objective: Approximately 5% of women suffer from recurrent vulvovaginal candidiasis (RVVC). It has been hypothesized that genetic factors play an important role in the susceptibility to RVVC. The aim of this study was to assess the effect of genetic variants of genes encoding for pattern recognition receptors (PRRs) on susceptibility to RVVC.Study design: For the study, 119 RVVC patients and 263 healthy controls were recruited. Prevalence of polymorphisms in five PRRs involved in recognition of Candida were investigated in patients and controls. In silico and functional studies were performed to assess their functional effects.Results: Single nucleotide polymorphisms (SNPs) in TLR1, TLR4, CLEC7A, and CARD9 did not affect the susceptibility to RVVC. In contrast, a non-synonymous polymorphism in TLR2  increased the susceptibility to RVVC almost 3-fold. Furthermore, the TLR2 rs5743704 SNP had deleterious effects on protein function as assessed by in silico analysis, and in vitro functional assays suggested that it reduces production of IL-17 and IFNγ upon stimulation of peripheral blood mononuclear cells with Candida albicans. No effects were observed on serum mannose-binding lectin concentrations.Condensation: This study demonstrates the association of susceptibility to RVVC with genetic variation in TLR2, most likely caused by decreased induction of mucosal antifungal host defense.Conclusion: Genetic variation in TLR2 may significantly enhance susceptibility to RVVC by modulating host defense mechanisms against Candida. Additional studies are warranted to assess systematically the role of host genetic variation for susceptibility to RVVC. Candida microorganisms, especially Candida albicans, often colonize the genital tract in women, and under certain conditions are responsible for mucosal inflammation , defined as at least three infections per year  on innate immune cells sense molecular moieties on the surface of microorganisms, and thereafter induce an intracellular signal that stimulates production of effector molecules such as cytokines or defensins. Two classes of PRRs have been reported to be the main recognition receptors for C. albicans: Toll-like receptors (TLRs) and C-type lectin receptors , CARD9 , TLR1 , TLR2 , and TLR4  on the susceptibility to RVVC.The inclusion of patients and controls in this study was approved by the Institutional Review Boards of the Radboud University Medical Centre, School of Medicine, Wayne State University and Hôpital Necker. Enrollment took place between January 2010 and December 2011. Patients gave written informed consent and the study was in accordance to the declaration of Helsinki.Enrolment of healthy controls for blood donations was approved by the Institutional Review Board of the Radboud University Medical Centre.C. albicans. Exclusion criteria were use of any immunosuppressive therapy (including steroids), diabetes, pregnancy, and HIV infection. EDTA venous blood was collected after obtaining written informed consent. Asymptomatic healthy controls without a history of vaginal Candida infections (N = 263) were recruited at Radboud University Nijmegen Medical Center, Nijmegen, Netherlands and gave written informed consent. All patients and controls were of Western-European genetic background.The patient cohort consisting of 119 RVVC patients were recruited at Wayne State University School of Medicine , Radboud University Nijmegen Medical Center  and Hôpital Necker . Patients were enrolled during episodes of acute vaginitis or, if asymptomatic, while receiving maintenance fluconazole therapy. Inclusion criteria for the study were: healthy women above 18 years of age, diagnosed with at least three documented episodes of VVC in a year, microbiologically validated and all caused by CLEC7A (DECTIN-1) Tyr328X (rs16910526) and CARD9 Ser12Asn (rs4077515) polymorphisms in the patients was screened by the TaqMan SNP assay C_33748481_10 and C_25956930_20, respectively, . The genotype for the TLR1 polymorphism Arg80Thr (rs5743611) was assessed with the TaqMan SNP assay C_27855269_10. The genotype of TLR2 Pro631His (rs5743704) was assessed by applying a predesigned TaqMan SNP assay C_25607736_10. The genotyping for the TLR4 polymorphisms Asp299Gly (rs4986790) and Thr399Ile (rs4986791) was performed with the TaqMan SNP assay C_11722238_20 and C_11722237_20, respectively. The TaqMan qPCR assays were performed on the 7300 ABI Real-Time polymerase chain reaction system (Applied Biosystems). Positive and negative controls were included in the assays.Genomic DNA was isolated from whole blood using the Qiagen  isolation kit and following the standard protocol. The genotype for the TLR2 protein information was obtained from Swissprot accession code O60603, and OMIM accession code 603028, using the MRS server1. We used the PROSITE server2 to retrieve information about the TLR2 protein domains. No protein structure is available for the complete TLR2 protein at the moment. However, the cytoplasmic TIR domain is known and can be found as PDB-file 1O77  was performed for 24 h, 48 h or 7 days. The incubation time varied for each cytokine: 24 h for IL-1β and IL-6, 48 h for IFNγ and IL-10, and 7 days for IL-17 (with the addition of 10% human serum). After the incubation time, cytokines were measured in the supernatants by ELISA . Detection limits were 40 pg/mL, except for the IFNγ ELISA (12 pg/mL). Mannose-binding lectin (MBL) concentrations in serum were measured by ELISA .Peripheral blood mononuclear cells (PBMCs) were isolated from 73 healthy volunteers by Ficoll-Paque gradient. All healthy volunteers gave written informed consent. 0.5 × 10TLR2 genotype on the in vitro cytokine production, a non-parametrical Kruskal–Wallis analysis was performed, and for the circulatory MBL measurement we used the Mann–Whitney U-test. Both analyses were done using GraphPad Prism version 4.00 for Windows, GraphPad Software, San Diego, CA, USA.For the analysis of the polymorphisms in the PRRs, statistical comparisons of frequencies were made between RVVC versus control subjects. We used SPSS 16.0 software to perform Chi-square tests and the 5% Confidence Intervals Odds ratio to calculate the risk. Furthermore, for the analysis of the effect of the CLEC7A) has previously been shown to be associated with an increased susceptibility to fungal infections, a first set of comparisons assessed the prevalence of CLEC7A and CARD9 polymorphisms in control individuals and patients with RVVC (Table 1). No effects of CLEC7A  and CARD9  polymorphisms on the susceptibility to RVVC have been observed. In a second set of experiments, the prevalence of polymorphisms in the genes coding for TLR1 , TLR2 , and TLR4  was also assessed. These analyses revealed that the polymorphisms in the TLR1 and TLR4 genes did not affect the susceptibility to RVVC. In contrast, the genotype for the Pro631His polymorphism on the TLR2 gene was associated with a 2.705-fold increase  in susceptibility to RVVC in the patient cohort. All genetic distributions are in Hardy–Weinberg equilibrium (Table 1).As a polymorphism in the gene encoding the CLR DECTIN-1 . To visualize the Pro631His polymorphism on the 3D structure of the TIR domain, we evaluated the homology model using the YASARA software. A screenshot of the 3D homology model is shown in Finally, the HOPE server predicted that due to the fact that the polymorphism introduces an amino acid with different characteristics, this would affect the function of the molecule. The wild-type residue proline is rigid, resulting in a characteristic backbone conformation that might be required at this position. Additionally, proline is more hydrophobic than histidine, and this may also influence the function of the molecule through loss of hydrophobic interactions on the surface of the protein. This hypothesis was also tested through a series of web servers to predict the pathogenicity of the Pro631His amino acid change. As shown in Supplementary Table TLR2 Pro631His polymorphism in further detail, cytokine production of PBMCs stimulated with heat-killed C. albicans was assessed in a group of healthy volunteers. The major limitation of this part of the study was that only two individuals in this group were heterozygous for the variant allele, which precludes drawing definitive conclusions. However, we observed that whereas the IL-1β, IL-6, and TNFα production was in the same range comparing the different genotype groups, both individuals bearing the mutated allele displayed a strongly diminished release of the T-cell derived cytokines IFNγ and IL-17 , known to be important for antifungal host defense .In order to assess the functional consequences of the  defense . In contCandida recognition (TLR2 is associated with increased susceptibility to RVVC. In silico assessment suggested functional consequences of the TLR2 polymorphism, and this hypothesis is supported by the decreased production of T-cell derived cytokines IFNγ and IL-17 in two individuals bearing the mutation. However, a definitive conclusion was not able to be drawn due to the low number of volunteers with TLR2 SNP identified in the functional studies.Vulvovaginal candidiasis is one of the most common infections in women. Despite known risk factors such as the hormonal status, diabetes, pregnancy or immunosuppressive therapy , the majognition  affects CLEC7A gene coding for the DECTIN-1 receptor (CLEC7A gene is associated with increased mucosal Candida colonization (Candida infections (Genetic variants in PRRs have been previously reported to influence predisposition to RVVC. This has been described in a family of patients with a complete deficiency of DECTIN-1, due to an early stop codon mutation in the receptor . Functioreceptor . In addireceptor . Moreovenization . Thus, wfections .CARD9 Ser12Asn polymorphism did not yield a significant association with RVVC susceptibility in the present study. Similarly, we have previously shown that this polymorphism does not influence the susceptibility to candidemia (CARD9 is an adaptor molecule mediating signals induced by DECTIN-1, but also other CLRs. Its role in antifungal immunity has been demonstrated both in knock-out mouse studies , as wellndidemia .Candida in particular, TLR2, TLR4, and TLR1 being most important in antifungal immunity (TLR1 polymorphisms have been recently shown to influence susceptibility to candidemia (TLR4 polymorphisms that have been previously associated with susceptibility to Gram-negative sepsis and other infections did not have a significant effect on susceptibility to RVVC (In addition to CLRs, TLRs are the second major family of PRRs involved in the recognition of fungi in general, and immunity . While Tndidemia , no such to RVVC .TLR2 Pro631His polymorphism induced an almost threefold increase in the susceptibility to RVVC. TLR2 is an important PRR for C. albicans recognition, activating innate immune responses both alone and in synergy with DECTIN-1 (in silico analysis using homology modeling and conservation analysis suggests detrimental effects of the mutation on the function of the receptor. This is supported by the study of TLR2 allele, both of them consistently produced very low amounts of the T-cell derived cytokines IFNγ and IL-17, mediators that are crucial for mucosal antifungal defense (TLR2 variant leads to reduced NF-κB activation.In contrast, the DECTIN-1 . The defDECTIN-1 , but no  defense . This obTLR2 polymorphism on cytokine production, we have also assessed its influence on the concentrations of MBL. MBL is a circulating receptor for mannose residues which activates the complement system and opsonizes Candida (TLR2 alleles, showing that the effect of the TLR2 Pro631His polymorphism on the RVVC susceptibility is independent of the production of MBL. Ideally, the cytokine analyses should be extended to assessment in lavage fluids or cells. However, these materials were not collected from the patients presented in this manuscript, and future studies should address this aspect.In addition to the effects of the  Candida . MBL def Candida . HoweverCLEC7A, CARD9, TLR1, and TLR4 polymorphisms had no impact, the TLR2 Pro631His polymorphism was associated with an almost 3-fold increase in susceptibility to RVVC. These data demonstrate the role of TLR2 genetic variation in innate immunity genes for RVVC, and future investigations are warranted in larger cohorts if possible to replicate and extend the results of the present study.In conclusion, in this study we provide evidence that polymorphisms in PRRs may play an important role in susceptibility to RVVC in otherwise healthy women. While http://www.frontiersin.org/journal/10.3389/fmicb.2014.00483/abstractThe Supplementary Material for this article can be found online at Click here for additional data file.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


PD-1) plays an important inhibitory role in anti-tumor responses, so it is considered as a powerful candidate gene for individual’s genetic susceptibility to cancer. Recently, some epidemiological studies have evaluated the association between PD-1 polymorphisms and cancer risk. However, the results of the studies are conflicting. Therefore, a meta-analysis was performed. We identified all studies reporting the relationship between PD-1 polymorphisms and cancers by electronically searches. According to the inclusion criteria and the quality assessment of Newcastle-Ottawa Scale (NOS), only high quality studies were included. A total of twelve relevant studies involving 5,206 cases and 5,174 controls were recruited. For PD-1.5 (rs2227981) polymorphism, significantly decreased cancer risks were obtained among overall population, Asians subgroup and population-based subgroup both in TT vs. CC and TT vs. CT+CC genetic models. In addition, a similar result was also found in T vs. C allele for overall population. However, there were no significant associations between either PD-1.9 (rs2227982) or PD-1 rs7421861 polymorphisms and cancer risks in all genetic models and alleles. For PD-1.3 (rs11568821) polymorphism, we found different cancer susceptibilities between GA vs. GG and AA vs. AG+GG genetic models, and no associations between AA vs. GG, AA+AG vs. GG genetic models or A vs. G allele and cancer risks. In general, our results firstly indicated that PD-1.5 (rs2227981) polymorphism is associated a strongly decreased risk of cancers. Additional epidemiological studies are needed to confirm our findings.Programmed cell death-1 ( PD-1), a member of the CD28/B7 superfamily of costimulatory molecules, is expressed on activated CD4+ and CD8+ T cells, natural killer T (NKT) cells, B cells, activated monocytes and some dendritic cell (DC) .–38.PD-1 cer risk . OverallPD-1.5 (rs2227981) were pooled together. Six of the studies were population-based and only one study was hospital-based. According to the ethnicity, six articles were researched about Asians and one study was about Caucasians. We conducted analyses for all genetic models and allele in overall group, Asians subgroup and population-based subgroup. Overall, we obtained significantly decreased cancer risks both in TT vs. CC , TT vs. CT+CC  genetic models and T vs. C  allele. However, no dramatic associations were found in the other genetic models  (I2 = 24.1%) and TT vs. CT+CC  genetic models. There were no significant associations in TT+CT vs. CC , TC vs. CC  and T vs. C  (I2 = 7.5%), TT vs. CT+CC  and T vs. C . However, still we had observed no significant associations in TT+CT vs. CC  and TC vs. CC   . When st= 59.1%) . When co= 61.5%) .PD-1.9 (rs2227982) and PD-1 rs7421861 polymorphisms were both discussed in four studies, which including 1,961 and 1,975 cases, and 2,390 and 2,403 controls, respectively. Overall, there were no significant associations between either PD-1.9 (rs2227982) . All the studies about these two polymorphisms are conducted in Asians. When concerning the control sources, there are two hospital-based and two population-based articles studied about the PD-1.9 (rs2227982) polymorphism, while three hospital-based and one population-based article studied about the PD-1 rs7421861 polymorphism.The 2227982)  or PD-1 s7421861  and cancI2 = 0.0%). Interestingly, an increased cancer risk was found in AA vs. AG+GG genetic model . In addition, there were no associations between cancer risk and AA vs. GG , AA+AG  vs. GG or A vs. G   .We performed both funnel plots and Egger’s tests for all genetic models and allele to assess the publication bias. Our results showed all the funnel plots were symmetrical distribution that suggested absence of publication bias –S6 Figs.PD-1 is an immune gene with potent inhibitory effects on immune cells. As an important gene for the “fine turning” of T lymphocyte activation and proliferation to affect host anti-tumor immunity, PD-1 merits more investigations. Many studies have reported that over expression of PD-1 is associated with poor prognosis in several tumors, which including breast, cervical, gastric, esophageal cancers and non-small cell lung cancer (NSCLC) [PD-1 is expressed on tumor specific T cells, when interacts with PD-Ls, expressed on tumor and immune cells, could extensively restricts host anti-tumor immunity and creates antitumor suppressive milieu [PD-1-PDLs interaction as an immunotherapy procedure to conquer immune-suppression associated with cancer condition [PD-1 polymorphisms and various cancers including breast, gastric, colorectal, lung and liver cancer, et al. However, the results are controversial. So we performed this meta-analysis to discuss the associations between PD-1 polymorphisms and cancer risk.It is known to us that  (NSCLC) –10, 39. e milieu , 41. AccPD-1.5 (rs2227981) polymorphism and cancer risks. Their results showed no association between PD-1.5 (rs2227981) polymorphism and total cancer risk, but revealed an increased digestive system tumor risk. However, we found that they wrongly included one study researched about the PD-1.3 (rs11568821) polymorphism and colon cancer risk [PD-1.5 (rs2227981) polymorphism compared with the prior meta-analysis were summarized in Previously, Mamat U et al. performed a meta-analysis  discussecer risk  in theirPD-1 polymorphisms and cancer risk. Therefore, our research mainly concerned on the case-control studies. In this study, association between PD-1.5 (rs2227981), PD-1.9 (rs2227982), PD-1 rs7421861 or PD-1.3 (rs11568821) and cancers risk were examined in all genetic models and allele, and all the results were summarized in PD-1.5, our results showed a significant decreased cancer risks both in TT vs. CC and TT vs. CT+CC genetic models for overall population, Asians and population-based controls, also significant decreased cancer risk was found in T vs. C allele for overall population. PD-1.5 located in exon 5, is a synonymous polymorphism that does not change final amino acid sequence of the protein. Thus these significant associations between PD-1.5 and cancers probably may be PD-1.5 variation linkage disequilibrium with other PD-1 gene polymorphisms that may lead to alter the PD-1 expression level [PD-1.5, TT genotype may reduce the cancers risk.In recent years, the application of the genome-wide association study (GWAS) in many types of diseases has exploded and lots of the GWASs about cancer risk were published. However, there is no GWAS focused on the on level . Recentlon level  reportedPD-1.9 (rs2227982) and PD-1 rs7421861 polymorphisms. It has been identified that PD-1.9, located in exon 5, is a non-synonymous SNP of PD-1, resulting the amino acid substitution from valine to alanine during protein synthesis, which probably lead to different structures and different functions of PD-1. As for PD-1 rs7421861, it is situated in intron 1 where a number of regulatory elements and splicing control elements exist [PD-1 rs7421861 may induce aberrant splicing, and further result in translational prevention [PD-1.9 (rs2227982) or PD-1 rs7421861 in all genetic models and alleles. The limited sample size may be an important reason of the results, and we should treat the results with caution. Further studies are also needed to determine the function of these two polymorphisms.We also investigated the ts exist , 46. Theevention –49. HowePD-1.3 (rs11568821) polymorphism in our meta-analysis. The PD-1.3 polymorphism was a guanine (G) to adenine (A) single nucleotide polymorphism (SNP) at nucleotide +7146 in the PD-1 intron 4. A region of PD-1 intron 4 was described as an enhancer-like structure containing binding sites for several transcription factors [PD-1.3 polymorphism in this region may affect the binding of the runt-related transcription factor 1 (RUNX1) and alter the transcriptional regulation and the efficiency of PD-1 gene [PD-1.3 polymorphism disrupted the binding site for RUNX1 transcription factors and resulted the impairment of PD-1 inhibitory effect and higher lymphocyte activity [PD-1.3 polymorphism may have increased tumor immunity capacity and decreased the susceptibility of cancers. Consistently, our results of PD-1.3 (rs11568821) polymorphism showed a decreased cancer risk in GA vs. GG, but an increased cancer risk was found in AA vs. AG+GG. Besides, no dramatic associations were found between AA vs. GG, AA+AG vs. GG genetic models or A vs. G allele and cancer risk. However, large scale and more rigorous analytical studies will be required to confirm the association between PD-1.3 polymorphism and cancer risk.In addition, we discussed the  factors . ExistinD-1 gene . Moreoveactivity . Hence, PD-1.3 (rs11568821) polymorphism may lead to insufficient statistical power to explore the real association. Secondly, the heterogeneities were significant in some genetic models and alleles for PD-1.5 (rs2227981) and PD-1.3 (rs11568821) polymorphisms. When we performed subgroup analyses stratified by ethnicity and control source, the heterogeneities in some subgroups were decreased or removed while in some subgroups were still existed. Thirdly, lacking of the original data limited our further evaluation of potential gene-gene, gene-environment, or even different polymorphism loci of the same gene, which all may affect cancer risk.There are some limitations should be addressed in this meta-analysis. First of all, the limited number of participants for PD-1.5 (rs2227981) polymorphism is associated with significantly decreased cancer risks both in TT vs. CC and TT vs. CT+CC genetic models, no matter for overall population, Asians subgroup or population-based subgroup, also the decreased cancer risk was found in T vs. C allele for overall population. No associations were found between the cancer risks and PD-1.9 (rs2227982) or PD-1 rs7421861 in all genetic models and allele. In addition, for PD-1.3 (rs11568821) polymorphism, we found different cancer susceptibility between GA vs. GG and AA vs. AG+GG genetic models, and no associations between AA vs. GG, AA+AG vs. GG genetic models or A vs. G allele and cancer risk. However, our results firstly revealed a significantly decreased risk between PD-1 polymorphisms and cancers, even though the data may be limited. Hence, large scale, well-designed epidemiological studies will be required to confirm our findings in the future.In summary, our meta-analysis suggested that the S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S1 Meta-Analysis on Genetic Association Studies Form(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.