VDR) gene polymorphisms affect the risk of prostate cancer. However, studies investigating the relationship between VDR gene polymorphisms (Cdx2 and ApaI) and prostate cancer risk are equivocal. Therefore, we conducted a meta-analysis of all the studies to review the evidence available.Vitamin D receptor  and 95 % confidence intervals (CIs) were analyzed to determine the association between VDR Cdx2 polymorphism. An additional 11 studies involving 2837 cases and 2884 controls were analyzed for the VDR ApaI polymorphism. Evidence failed to support the role of VDR Cdx2 and ApaI polymorphisms in prostate cancer. For Cdx2, the pooled OR was 1.11 (95 % CI = 0.93–1.33) for AA vs. GG genotypes, 0.97 (95 % CI = 0.88–1.06) for GA vs. AA genotypes, 0.99 (95 % CI = 0.91–1.08) for AA + GA vs. GG, and 1.12 (95 % CI = 0.95–1.31) for AA vs. GA + GG. No significant relationship was observed in any subgroup analysis based on ethnicity, controls, and Hardy–Weinberg equilibrium (HWE). ORs for the ApaI polymorphism were similar.The meta-analysis included 10 studies involving 4979 cases and 4380 controls to analyze the VDR Cdx2 and ApaI polymorphisms are not associated with prostate cancer. Additional evidence is required to confirm this conclusion.VDR  Prostate cancer ranks second among cancers diagnosed worldwide and sixth among cancer-related deaths in males. In 2012, more than 1.1 million cases were newly diagnosed worldwide. Prostate cancer accounts for 15 % of all cancers in men, and nearly 759,000 are reported in developed countries. In 2012, prostate cancer ranked fifth among cancer-related deaths in men, accounting for nearly 307,000 deaths or 6.6 % of all cancer-induced deaths in males [BRCA1 and BRCA2 mutations increase the risk for ovarian and breast cancer as well as prostate cancer [HPC1), androgen and vitamin D receptors have been linked to prostate cancer [The role of genetics in prostate cancer has been the focus of research attention in recent years. e cancer . Heredite cancer . Genome-e cancer , 10 repoFokI, BsmI, ApaI, Cdx2, and TaqI [BsmI, TaqI, and FokI polymorphisms in prostate cancer is not established [ApaI and Cdx2 polymorphisms in prostate cancer risk are not validated [ApaI compared with homozygous AA carriers [Cdx2 polymorphism significantly increased the prostate cancer risk among Hispanic populations carrying the SRD5A2 V89L VV genotype [ApaI and Cdx2 SNPs [The role of testosterone and vitamin D in prostate cancer is mediated via vitamin D receptor (VDR). The hormonally active form of vitamin D1, 25-dihydroxyvitamin D, inhibits cancer progression . Vitaminand TaqI –18. Howeablished , 20. Simalidated , 21–28. genotype . Howeverdx2 SNPs .Cdx2 and ApaI polymorphisms in prostate cancer risk by conducting a meta-analysis of all the eligible case-controlled studies.The discrepancies may be attributed partly to statistical weakness, heterogeneity, population diversity, minimal effect of polymorphisms, and publication bias. We, therefore, investigated the role of VDR ApaI and Cdx2 polymorphisms and prostate cancer susceptibility, published through September 2015. We used combinations of the following keywords: ‘prostate cancer’, ‘VDR’ or ‘vitamin D receptor’, ‘ApaI’ or ‘rs7975232’, ‘Cdx2’ or ‘rs11568820’, and ‘polymorphism’, ‘variant’, or ‘mutation’. Two independent investigators (Kewei Wang and Guosheng Wu) performed the search. Additional articles were retrieved via manual searches of reference lists in the studies identified initially. Our search was not restricted by publication date or language. Selected articles are listed in Table P value). Other eligible studies were retrieved for additional review and data extraction. All the investigators were qualified and trained in literature search, statistical analysis, and evidence-based medicine.We searched PubMed, EMBASE, and ISI Web of Science databases for genetic association studies involving VDR Cdx2 and ApaI polymorphisms and prostate cancer risk; (2) clinical studies; (3) case–control studies; (4) studies investigating diseases confirmed histologically, pathologically and/or radiologically; (5) adequate genotype distributions to facilitate estimation of OR with 95 % CI; and (6) most recent or complete studies. The exclusion criteria were:: (1) studies containing overlapping data; (2) missing genotype or allele frequencies; (3) absence of case controls; (4) studies not analyzing VDR Cdx2 and ApaI polymorphisms in prostate cancer susceptibility; (5) studies investigating progression, severity, phenotype modification, response to treatment, or survival; (6) inadequate data extraction; or (7) missing genotype frequencies.The inclusion criteria were: (1) studies evaluating VDR Cdx2 and ApaI polymorphisms, and prostate cancer risk. The Z test was used to evaluate the significance of pooled OR. P value less than 0.05 was deemed significant. Homozygote, heterozygote, recessive and dominant models were used to determine the association of Cdx2 and ApaI polymorphisms with prostate cancer risk.ORs with 95 % CIs were used to measure the relationship between VDR 2 statistic [P < 0.10 or I2 > 50 % suggested statistically significant heterogeneity. A random effects model was used to calculate the pooled OR estimates. In other cases, a fixed effect model was used [Statistical heterogeneity was evaluated using chi-square-based Q-statistic  and I2 statistic . P < 0.1was used .Sensitivity and subgroup analyses were used to explore the sources of heterogeneity among studies. Sequential exclusion of individual studies facilitated the evaluation of stability and sensitivity of the results. Subgroup analyses were based on ethnicity, controls and HWE.P value less than 0.05 in Egger’s test indicated significant publication bias.Begg’s funnel plots were used to determine publication bias in studies. Linear regression asymmetry was tested using the procedure described by Egger et al. . An asymP values were two-sided. The reliability and accuracy of the results were ensured by two authors independently evaluating the data with the same software.The statistical tests were conducted using STATA statistical software . All Cdx2 polymorphism and prostate cancer risk, and 11 studies involved 2837 cases and 2884 controls related to VDR ApaI polymorphism.The search terms returned 292 publications. We excluded 266 studies unrelated to Vitamin D receptor (VDR) gene polymorphism, three studies unrelated to prostate cancer –36, and Cdx2 polymorphism. VDR ApaI polymorphisms were investigated in Caucasians in four studies. Six studies involved Asians, and two involved African-Americans. Ten studies involved population samples, and six were hospital-based. PCR-RFLP and TaqMan assays were used to study the polymorphisms. The genotype distributions were not in HWE among the controls in two studies investigating VDR Cdx2 [ApaI [The sample size ranged from 28 to 1117 individuals. Six of the eligible studies involved Caucasians and four were conducted in other ethnic groups to investigate VDR VDR Cdx2  and VDR x2 [ApaI , 16, 43.Cdx2 polymorphism was not significantly associated with prostate cancer risk in the pooled meta-analysis of all the eligible studies . Subgroup analyses based on ethnicity, source of control, and HWE in controls, revealed no significant association.As shown in Table ApaI polymorphism was not significantly correlated with prostate cancer risk in pooled analysis of eligible studies . Subgroup analyses based on ethnicity, source of controls, and HWE in controls, revealed the absence of prostate cancer risk with VDR ApaI polymorphism.As shown in Table ApaI polymorphism . Sensitivity analysis was conducted by excluding individual studies to determine heterogeneity. Sequential exclusion of individual case-controlled study revealed similar results statistically, indicating the stability and sensitivity of the meta-analysis (data not shown).Significant heterogeneity was found in AA vs. Aa genetic model of VDR Cdx2 polymorphism.Population and subgroup analysis revealed no significant heterogeneity in terms of VDR Cdx2 polymorphism  and VDR ApaI .Symmetrical Begg’s funnel plots indicated the absence of publication bias in the overall meta-analysis Fig. . Egger’sGenetic polymorphisms play a key role in the pathophysiology of disease. Genome-wide association studies (GWAS) reported more than 90 common SNPs  with established relationship involving insignificant alterations  in prostate cancer susceptibility –47. OverFokI, BsmI, ApaI, TaqI, and Cdx2, are associated with ovarian [VDR is a nuclear receptor regulating bone mineral homeostasis, mammalian hair cycle, and compound detoxification. It has recently been found to prevent tumorigenesis by inhibiting cell proliferation and differentiation, and inducing apoptosis. Previous studies demonstrated that VDR gene polymorphisms, which include  ovarian , skin [4 ovarian , breast  ovarian , and col ovarian .VDR transcription in intestine [The G-to-A polymorphism involving a Cdx2-binding site in the 1e promoter region, mediates ntestine . The strntestine . Thus, Cntestine .Cdx2 polymorphism prevents osteoporosis [ApaI polymorphisms (in intron 8) at the 3′ untranslated region (UTR) are in strong linkage disequilibrium (LD) [Cdx2 and ApaI polymorphisms in prostate cancer risk, with inconclusive results. Therefore, we conducted a meta-analysis to establish the association between VDR Cdx2 and ApaI polymorphisms, and prostate cancer risk.oporosis . The Apaium (LD) . Nonetheium (LD) . SeveralCdx2 and ApaI polymorphisms, and prostate cancer risk. Our results suggest that these polymorphisms do not increase the risk of prostate risk in genetic models, which was consistent with a previous meta-analysis [Cdx2 and ApaI polymorphisms, and prostate cancer risk in any comparative studies.Our meta-analysis, including 6427 cases and 6039 controls from 16 case-controlled studies, evaluated the association between analysis . HoweverCdx2 and ApaI polymorphisms in prostate cancer was unclear due to ethnic variation in genotypes, controls and subjects, and genotyping techniques [Cdx2 AA genotype is most frequently found in African-Americans (58.9 %) [The role of VDR chniques . The VDR(58.9 %) , while t(58.9 %) .ApaI genotype AA is the most prevalent in African-Americans (40.2 %) [The VDR (40.2 %) , while t(40.2 %) . HoweverCdx2 polymorphism and eight involving VDR ApaI polymorphism) which included subjects from more representative populations to determine potential gene association in tumorigenesis.Furthermore, a few hospital-based studies did not support the association of increased risk with VDR polymorphisms compared with normal controls , 58, in Cdx2 and ApaI polymorphisms, and prostate cancer risk in previous studies is attributed to differences in lifestyle and disease prevalence as well as limited sample size [The relationship between VDR ple size –62. Furtple size .However, the risk factors underlying prostate cancer are related to each other. Similar gene polymorphisms may still result in different phenotypes, because the penetrance of the mutation depends on the interaction with other polymorphisms and exposure to specific environment.Cdx2 polymorphism in our meta-analysis. Different genotype distributions and population stratification may also alter genotype-phenotype associations.Genetic heterogeneity in meta-analysis of studies investigating genetic polymorphisms and various diseases is not surprising. However, no heterogeneity was observed among studies investigating the VDR ApaI polymorphism.Furthermore, a number of factors affect heterogeneity. Different studies select subjects for control groups based on different definitions, resulting in heterogeneity observed in our meta-analysis. We investigated whether the heterogeneity might be explained by potential confounding factors such as age, smoking, drinking, androgen levels, and other clinical characteristics. However, no reliable results were available due to lack of access to individual data involving these variables. Similar heterogeneity was observed with the VDR Cdx2 and ApaI polymorphisms are needed to facilitate subgroup analyses. Environmental interaction with VDR Cdx2 and ApaI polymorphisms and its role in prostate cancer risk needs to be validated.Cancer is a complex disease, and is triggered by genetic factors as well as environmental impact (UV exposure), gene interactions, and lifestyle  –71. InteCdx2 polymorphism in prostate cancer risk involved Caucasian population. Therefore, evidence based on large controlled studies involving a wide range of ethnic and population groups is needed to re-evaluate the association between specific SNPs and prostate cancer risk.The study limitations of our meta-analysis are as follows. First, in subgroup analyses based on ethnicity, the population sample size was comparatively small, which may affect the statistical power in determining the significance of the relationship. Second, our results were not adjusted for variables such as age, smoking, drinking, obesity, gene-gene interactions, and environmental factors, due to lack of access to the original study data. Finally, most studies investigating the VDR Cdx2 and ApaI polymorphisms are not linked to prostate cancer susceptibility in the overall population. Epidemiological studies with large sample sizes including a wide range of ethnic populations and functional parameters are needed to reinforce our findings.Our findings suggest that VDR


Plasminogen activator inhibitor −2 (PAI-2) is an important molecular that plays a crucial role in vascular homeostasis and constitutes a critical response mechanism to cardiovascular injury, such as atherosclerosis, coronary artery disease (CAD).PAI-2 gene and CAD and its prognoses. The three variants  of the PAI-2 gene were detected in 407 patients with CAD and 518 control subjects. All patients with CAD underwent one-year follow-up for major adverse cardiac events (MACE).The aim of the current study was to explore the association between the variants in P = 0.003, 28.1 % vs.21.7 %, P < 0.001, respectively). Multifactor logistic regression analysis showed that the TT genotype of rs8093048 was a risk factor for CAD . In addition, the follow-up data showed that CAD patients with rs8093048 TT genotype had significantly higher rate of refractory angina and MACE than those with CC or CT genotype . Cox regression analysis showed that rs8093048 TT genotype was the risk factor for the MACE .The frequencies of the TT genotype and T allele of rs8093048 was significantly higher in CAD patients than that in control subjects (7.6 % vs.3.5 %, PAI-2 gene was associated with CAD and recurrent coronary event risk in Chinese Han population, in Xinjiang.We firstly found that the variant of  The plasminogen activator (PA) system plays a key role in vascular homeostasis and constitutes a critical response mechanism to cardiovascular injury, such as atherosclerosis, coronary artery disease (CAD), myocardial infarction (MI) and restenosis . The cenPAI-2 gene consists of 8 exons spanning 16.18 kb on the long arm of chromosome 18 .t test. Categorical data and distribution of genotypes and alleles were shown as percentages (%) and the differences between the two groups were assessed by chi-square test. Logistic regression analysis was performed to assess the contribution of the major risk factor to CAD and the value was shown as odds ratio (OR) and its 95 % confidence interval (CI). In addition, the COX regressive analysis was used to assess the clinical prognosis among different genotype of Flotillin-2 gene. P < 0.05 was considered to indicate a statistically significant difference.All analyses were performed using the computer software Statistical Package for Social Sciences-SPSS for Windows (version 17.0). Hardy-Weinberg equilibrium was assessed by using chi-square analysis. Continuous data were expressed as mean ± standard deviation (SD) and the differences between the CAD patients and the control participants were assessed by independent samples P = 0.026). However, the percentage of individuals with EH, DM and smoking were significantly higher in CAD patients than that in control subjects . No significant differences in BMI, pulse and concentration of TC, TG, LDL-C were observed between the two groups  were participated in this study. There were no differences in age between CAD patients and control subjects, suggesting that the study was an age‑matched case‑control study. The concentration of HDL-C was significantly lower in patients with CAD than that in control subjects . The frequency of genotype and allele of PAI-2 gene in CAD patients and controls were shown in Table PAI-2 gene between CAD patients and controls. The PAI-2 gene rs8093048 TT genotype and T allele distribution was significantly higher in CAD patients than that in control subjects . For rs9946657 and rs9320032, we did not found any significant difference in the genotypic and allelic distribution of PAI-2 gene between CAD patients and controls.The genotype distribution of the three SNPs in P = 0.017) , DM, and smoking were the risk factors for CAD. Following adjustments for DM, EH, TC, LDL-C, HDL-C, and smoking, the subjects with T allele of rs8093048 (TT + CT) had a significantly higher risk of CAD   Table .Table 4TPAI-2 gene was associated with CAD and its prognosis in Chinese Han subjects. Individuals with TT genotype of rs8093048 had significantly higher risk of CAD and worse prognosis than that with CC or CT genotype. The rate of refractory angina was significantly higher in CAD patients with TT genotype than that with CC or CT genotype. The results demonstrated that the polymorphism of PAI-2 gene may be as a marker of CAD and its prognosis.In the current study, we observed that the variation in the PAI-2 is an important molecular of the serpin superfamily. It’s an efficient inhibitor of t-PA and u-PA and an important regulatory element in fibrinolysis. To maintain normal blood flow, fibrinolysis and hemostasis should exist in a precise balance in which fibrinolysis restricts excessive blood clots and hemostasis prevents excessive blood loss. Because serine proteases in both fibrinolysis and hemostasis are the key enzymes, both processes are primarily controlled by serine protease inhibitors  –20. GenePAI-2 gene may be a candidate gene of CAD in Chinese Han population. It was consistent with the previous researches. Cerrahpasa et al. found that AA genotype of the PAI-2 gene was found to be more frequent among those subjects with MI [PAI-2 polymorphism reference allele with recurrent cardiovascular disease risk [PAI-2 gene Ser/Cys413 polymorphism is associated with CAD, the C allele is a risk factor for CAD and the G allele is a protective factor for CAD [PAI-2 and acute coronary syndrome [PAI-2 polymorphism was associated with susceptibility and damage index score in systemic lupus erythematosus [PAI-2 gene was also associated with antiphospholipid syndrome [PAI-2 gene in this system.But so far, the reason and mechanism of PAI-2 and CAD are unclear. We firstly indicated that  with MI . James ease risk . Zhao et for CAD . Howeversyndrome . The conematosus . Moreovesyndrome . These dPAI-2 gene with the CAD. As we know, SNPs are the most abundant form of genetic variations and have a great potential for mapping genes underlying complex genetic traits. But their effects were micro-effect. Much more studies of the other SNPs are needed to investigate the mechanism of CAD and PAI-2 gene. Secondly, the level of plasma concentration of PAI-2 was not measured in our study because of their low concentrations. However, there was an advantage in the present study what the sample size was relatively large. It was better to indicate the association between PAI-2 gene and CAD.There were certain limitations in our study. Firstly, we only detected the association between the 3 SNPs in PAI-2 gene may be associated with the susceptibility to CAD and its prognosis in Chinese Han population. Individuals with rs8093048 TT and CT genotype had significantly higher risk of CAD and worse prognosis than that with CC genotype. The rate of refractory angina was significantly higher in CAD patients with TT genotype than that with CC or CT genotype.In conclusion, we are more convinced that the variant in


OPN) gene polymorphisms, rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) and cancer risk in the Chinese population. However, the results are controversial and indefinite. We therefore carried out a meta-analysis to derive a more precise estimation of these associations. The PubMed database was systematically searched to identify potentially eligible reports. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations between 3 OPN gene polymorphisms and cancer risk in a Chinese population. A total of 10 articles involving 2,391 cases and 3,007 controls were evaluated. The pooled OR indicated that OPN rs17524488 (−156 GG/G) polymorphism was significantly associated with cancer risk in Chinese population. In a stratified analysis by source of control, significant associations were also observed among rs17524488 (−156 GG/G) and rs11730582 (−443 T/C) polymorphisms and cancer. In addition, a stronger association was observed between rs9138 (C/A) polymorphism and cancer risk. In conclusion, this meta-analysis suggests that OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms may be associated with cancer susceptibility in the Chinese population. Nevertheless, further investigation on a larger population covering different ethnicities are warranted.Previous studies have investigated the association between osteopontin ( The estimates of newly diagnosed cancer cases/cancer-related deaths in worldwide and China were approximately 14.1/8.2 million in 2012 and 3.37/2.11 million in 2011, respectively1Osteopontin (OPN) is a phosphorylated acidic glycoprotein with several functions in different physiological and pathological processes, including bone turnover, wound healing, ischemia, inflammation, autoimmune responses, and tumorigenesis, mediated by stimulation of certain signaling pathways via binding to cellular receptors, integrins, and CD44 variants78Overexpression of OPN has been described in several conditions in which basic inflammatory processes are activated, such as arthritis14The gene encoding OPN, also known as secreted phosphoprotein 1 (SPP1), is mapped on human chromosome 4q21-q25, together with other members of the SIBLING family of proteins, bone sialoprotein, and dentin matrix protein-1, which share some structural characteristicsrs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms are most frequently studied.More than 10 SNPs have been identified in the OPN promoter. These polymorphisms may affect the transcriptional activity of OPN and some of them are thought to be genetic risk factors for disease susceptibility1718Considering the impact of the cancer risk potentially resulting from OPN gene, a number of studies have explored the association between these polymorphisms and cancer. However, individual studies have yielded inconsistent or conflicting findings, possibly caused by limitations associated with an individual study. To shed light on these contradictory results and to more precisely evaluate the relationship among OPN gene polymorphisms and cancer risk, we performed a meta-analysis of 10 published studies202122232425262728OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms and cancer risk. Eligible studies were found by searching the PubMed database for relevant reports published between 2010 and 2014. The search terms were “Osteopontin”, “polymorphism”, and “cancer”. In addition, the references of all retrieved articles were also manually searched for additionally relevant publications. The inclusion criteria were as follows: (1) evaluating the association between OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms, and cancer risk in a Chinese population; (2) case–control study; (3) and sufficient information  for calculating the pooled odds ratios (OR) with 95% confidence intervals (CI).We did our best to include all case–control studies published until date, regarding the association between Data included the following: first author, publication year, country, cancer type, source of control, each genotype frequency of the case and control groups, genotype methods, and the Hardy–Weinberg equilibrium (HWE) value in the control group.OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms and cancer. The pooled OR was estimated for rs17524488 (−156 GG/G) by homozygous (GG vs. GG/GG) and recessive models [GG vs.  (GGG + GG/GG)] as well as the allele model (G vs. GG); rs11730582 (−443 T/C) by homozygous (CC vs. TT) and recessive models [CC vs. (CT + TT)] as well as the allele model (C vs. T); and rs9138 (C/A) by homozygous (AA vs. CC), and recessive models [AA vs. (AC + CC)] as well as the allele model (A vs. C).Odds ratios (OR) with 95% confidence intervals (CI) were assessed for determining the relationship between Q-testZ-test. If P > 0.10 for the Q-test, a lack of heterogeneity among studies was found, meanwhile the fixed effects model should be used, otherwise, the random effects model should be used31P < 0.05 was considered significant. Sensitivity analysis was performed on excluded individual studies to assess the stability of the results. Publication bias was assessed by both Egger’s test and Begg’s testHeterogeneity was evaluated using a chi-square-based rs17524488 (−156 GG/G) polymorphism, 7 studies were available, including a total of 2,130 cases and 2,644 controls. For the rs11730582 (−443 T/C) polymorphism, 8 studies involved a total of 2,241 cases and 2,857 controls. For the rs9138 (C/A) polymorphism, 2 studies involved a total of 418 cases and 424 controls. Among these, 2 studies focused on gastric cancer. The distribution of genotypes among controls was consistent with HWE in all but 2 studies20202122232425262728OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms and cancer risk are presented in rs17524488 (−156 GG/G) polymorphism, significant association was observed in all cancer-type combined studies . Subgroup analysis by source of control showed that statistically significant associations were present in PB . Two studies20SNP.Results of rs11730582 (−443 T/C) polymorphism, significant association with cancer risk was observed in PB subgroup . For the rs9138 (C/A) polymorphism, significant relationship was detected overall . To our regret, no association was found between gastric cancer and OPN rs17524488 (−156 GG/G) or rs11730582 (−443 T/C) polymorphism.For the rs17524488 (−156 GG/G) (rs11730582 (−443 T/C), a single study named Mu et al.rs9138 (C/A), the sensitivity analysis was not examed. Egger’s and Begg’s tests were performed to assess publication bias and the funnel plot symmetry was examined. Finally, no proof of publication bias was obtained  . Howeverobtained , 9.OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms and cancer risk using a meta-analysis to obtain a powerful conclusion. To the best of our knowledge, this is the first meta-analysis providing comprehensive insights into the effects of the OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms and risk associated with all types of cancer in a Chinese population. Our meta-analysis included 2,391 cases and 3,007 controls202122232425262728The overall goal of a meta-analysis is to combine the results of previous studies to arrive at a summary conclusion about a body of research. It is most useful in summarizing prior research when individual studies are too small to yield a valid conclusion. In this study, we analyzed the associations between rs17524488 (−156 GG/G) polymorphism in the OPN promoter region, the overall results suggested that the subjects with G allele showed decreased susceptibility to cancer in a Chinese population. Moreover, individuals carrying either −156 GG or −443 CC genotype may have lower cancer susceptibility. However, people with AA genotype may have decreased cancer risk than CC-, CT, or CC + CT carriers. Considering that the previous single-institution study for cancer had a small sample size and may not justify the significance of current work, further studies are needed to clarify the effect of the 3 polymorphisms on the risk of cancer. A possible explanation for this phenomenon is that different polymorphisms may exert different effects on gene function, subsequently resulting in varying cancer susceptibility. Furthermore, a single gene or a single environmental factor is not likely to have a large effect on cancer susceptibility. Complex interactions between several genetic and environmental factors may be involved in cancer development.For the rs11730582 (−443 T/C) polymorphism, which suggested our study may be poorly powerful and stable. Finally, we also could not integrate different studies to look at the association between these three OPN SNPs and one specific cancer type, owning to insufficient publications. If there have a number of studies related different cancers in the future, this work may be carried out. In contrast, some advantages should also be highlighted. Our analysis comprehensively and systematically sheds light on the relationship between OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms and the susceptibility to cancer in the Chinese population. Additionally, due to the larger sample size, our meta-analysis increases the power and plausibility of our conclusion when compared with previous, individual studies. Finally, the studies included in this analysis were published between 2010 and 2014; thus, these studies are quite recent.Meta-analysis has been recognized as an effective method to answer a wide variety of clinical questions by summarizing and reviewing previously published, quantitative research. However, some limitations in our meta-analysis should be mentioned. First, our results were based on unadjusted estimates; more accurate outcomes would result from adjustments for other confounders such as gender, age, body mass index, lifestyle, and so on. Second, the studies included in this analysis were insufficient, especially in terms of a subgroup analysis. Thus, potential publication bias is very likely to exist, in spite of no evidence obtained from our statistical tests. Third, language of studies was limited to English, which may result in potential language bias. Fourth, a comparison of mRNA expression levels of the OPN gene between cancer and normal tissue should have been reported and included, which would better explain genetic function. Next, inter-gene and gene-environment interactions had not been evaluated owing to the absence of original data. Fifth, our study focused on Chinese people, other ethnicities should be reported and included. Sixth, a single studyOPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms are associated with cancer risk in the Chinese population. Larger sample sizes of different ethnic populations are required to confirm our findings.In summary, our meta-analysis suggests that How to cite this article: Mi, Y. et al. OPN gene polymorphisms, rs17524488 GG/G, rs11730582 T/C, and rs9138 C/A, and cancer risk in a Chinese population. Sci. Rep.5, 14164; doi: 10.1038/srep14164 (2015).


To investigate the association of a coronary artery disease (CAD) risk SNP rs6903956 with asymptomatic hyperuricemia (aHU) susceptibility in Han Chinese.Two hundred and twenty one patients with aHU and 447 healthy controls were recruited for this study. SNP rs6903956 were genotyped using TaqMan probe.p <0.001) in our Han Chinese aHU cohort. Multivariate logistic regression analysis indicated that rs6903956 might be an independent risk factor for aHU susceptibility  after adjustment for some well- known CAD risk factors including age, gender, body mass index, smoking, hypertension, diabetes mellitus, abnormal glycometabolism, lipid abnormality and alcohol intake. No significant genotype-specific difference in uric acid levels was observed in aHU patients and controls.The overall genotype and allele frequency distribution of the rs6903956 showed significant difference between aHU cases and controls . AA genotype of rs6903956 was significantly associated with aHU (OR = 8.672, 95% CI 2.811-26.753, Our findings are the first to establish a genetic link of a CAD-associated rs6903956 with aHU in a Han Chinese population, providing the genetic evidence to support the close relationship between hyperuricemia and CAD. Hyperuricemia (HU) is present in 5-30% of the general population and has been increasing around the world probably due to prolonged life expectancy, lifestyle and dietary changes, and the usage of certain drugs . HU is tAmong them, the relation between HU and CAD has been a topic of much interest in worldwide recently. The growing numbers of epidemiologic and experimental evidence have suggested that elevated level of serum uric is an independent risk factor for CAD incidence and mortality . AlthougTRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, etc.[ABCG2, PDZK1, SLC16A9, SLC2A9,SLC22A11, SLC22A12 etc. were of similar magnitude in individuals of non-European ancestry [SLC2A9 and hURAT1 contributed to the HU susceptibility in Han Chinese populations [ABCG2, PDZK1, SLC22A12 have also been linked to plasma lipoprotein (a) levels or hypertension, two most significant known risk factors for CAD [In addition to dietary and deficiency of the enzyme uricase, the varying levels of uric acid in human population are influenced by genetic factors. To date, Genome-Wide association (GWA) studies have identified and replicated 28 genetic loci that are strongly associated with serum uric acid concentrations in European ancestry including 18 new regions in or near ulations -12. Inte for CAD -15. ThesC6orf105 contributed to CAD susceptibility in Han Chinese  [Recently, GWAS study identified that a novel strong risk locus of rs6903956 in  = 1.51) . We therp < 0.05). Age and C-reactive protein was equally distributed between the two groups . aHU also have a higher genotypic frequency for the homozygous AA genotype than healthy controls . In codominant, dominant and recessive model, rs6903956 AA genotype was significantly associated with aHU susceptibility in our cohort   expression in cultured endothelial cells. TFPI is a key natural inhibitor of coagulation and play an important role in maintaining normal blood flow and endothelial cell function [C6orf105 mRNA expression in CAD patients [C6orf105 hence affect TFPI expression by altering ADTRP, resulting in endothelial cell dysfunction and abnormality of coagulation, which might explain rs6903956 contribute to CAD susceptibility. However, the mechanisms involved in the association of rs6903956 and aHU remains unclear. The heritability of serum urate concentrations is estimated at 40 − 70% [The rs6903956 is located in intron 1 of function . The deffunction . Given tpatients , it is p40 − 70% . PreviouHalf of aHU patients in current study are >52 years who had been exposed to a greater cardiovascular risk but still lack of any clinical symptom of CAD, supporting that these patients are a good asymptomatic hyperuricemia cohort to study the genetic link between HU and CAD; however, we could not exclude the possibility that some subclinical CAD patients were still mixed in this study. Therefore, further prospective studies in a larger population with longer follow-up are needed to confirm the genetic link between HU and CAD and the potential role of this SNP in acid homeostasis.To explore the potential genetic link between HU and CAD, a total of 221 asymptomatic hyperuricemia (aHU) patients and 447 health volunteers from Gaoyou rural district of Jiangsu Province, China were recruited for this study. aHU were defined as: 1) people with serum uric acid levels >420 μmol/L in man and post-menopausal woman, and as >350 μmol/L in premenopausal woman; 2) these patients never suffered from gout, and no self-reported history of CAD and/or any symptom and sign of CAD after carefully physical examination and medical history inquiry . HealthyGenomic DNA was obtained from the peripheral blood leukocytes using the PureGene DNA Blood Kit . The SNP rs6903956 was genotyped by TaqMan probe . The reaction mix was made from 20 × SNP genotyping assay, 2 × TaqMan Genotyping Master Mix, no AmpErase UNG, and DNA-free water. The final reaction volume per well is 5 μL containing 1 × SNP genotyping assay, 1 × TaqMan Genotyping Master Mix and about 20 ng DNA for a 384-well plate. The PCR reaction was performed according to the manufacturer’s protocol using the Applied Biosystems 7900HT Fast Real-Time PCR System: Enzyme Activation at 95°C for 10 minutes; denature at 95°C for 15 seconds, extension at 60°C for 1 minute, a total of 40 cycles. Post-PCR plate read and analysis were performed by Sequence Detection System software version 2.4 (Applied Biosystems).Genotypes were tested for Hardy-Weinberg equilibrium among all participants using a Chi-square test. Allele and genotype frequencies of rs6903956 were obtained by direct counting and the distributions comparison was performed by the Chi-square test. Differences in selected demographic continuous variables among groups were evaluated by one-way analysis of variance (ANOVA) or the Kruskal-Wallis H test. Categorical variables including sex, smoking status, alcohol consumption status, hypertension status, diabetes status were compared among the genotypes of rs6903956 using a Chi-square test. The association of rs6903956 genotype and aHU risk were estimated using codominant model (compared three genotype), dominant model (defined as GG vs. GA + AA) and recessive model (defined as GG + GA vs. AA), respectively. Odds ratios (OR) with their 95% confidence intervals (CI) were reported. A multivariate logistic regression analysis was used for association analyses with adjustments for age, gender, BMI, smoking, hypertension, and diabetes mellitus. P-value < 0.05 was considered statistically significant.http://hydra.usc.edu/gxe/_vti_bin/shtml.dll/request.htm). Considering rs6903956 minor allele frequency of 10% that was obtained in Han Chinese CAD patients [The statistical power calculation for the case–control analysis was performed using Quanto software (patients , our sam


NAD(P)H:quinone oxidoreductase 1 (NQO1), an obligate two-electron reductase, plays an important role in reducing reactive quinones to less reactive and less toxic hydroquinones. Genetic variations in NQO1 gene that impede its enzyme function may be considered as putative risk factor for cancer. Numerous studies have been performed to investigate the association between NQO1 Pro187Ser polymorphism and bladder cancer risk; nevertheless, the results remain controversial.We indentified eligible publications from PubMed, Embase and CBM databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to access the strength of the associations. False-positive report probability (FPRP) analysis was also performed for all statistically significant findings.We collected a total of 15 studies including 4298 cases and 4275 controls in the final meta-analysis. Overall, the NQO1 187Ser carriers were associated with an increased bladder cancer risk . Stratification analyses showed a statistically significant association among Asians , never smokers , hospital-based studies , studies with genotyping performed by PCR-RFLP under all genetic models, and studies with minor allele frequency >0.30 , respectively.Despite some limitations, our meta-analysis provides sufficient evidence that NQO1 Pro187Ser polymorphism may contribute to bladder cancer risk. These findings need further validation in well-designed prospective studies with larger sample size and different ethnicities, especially for Asians. Schistosoma hematobium infection are well-known etiologic factors for bladder cancer , MAF , and smoking status (never smokers and ever smokers). Any disagreements were resolved by discussions between the two authors until consensus reached.NQO1 Pro187Ser polymorphism and bladder cancer risk was evaluated by homozygous model (Ser/Ser vs. Pro/Pro), heterozygous model (Pro/Ser vs. Pro/Pro), recessive model [Ser/Ser vs. (Pro/Ser + Pro/Pro)], dominant model [(Pro/Ser + Ser/Ser) vs. Pro/Pro] as well as allele comparison (Ser vs. Pro). Goodness-of-fit chi-square test was used to test deviation from HWE and P<0.05 was considered as departure from HWE. Chi square-based Q-test was used to evaluate the between-study heterogeneity. Effect of heterogeneity was also quantified with the I2 statistic which measures the degree of between-study inconsistency. I2 lies between 0 to 100% with higher values indicating a greater degree of heterogeneity [P value of the heterogeneity test was ≥ 0.10 or I2 < 50% [The association between ogeneity . Fixed-eI2 < 50% ; otherwiI2 < 50% . PotentiI2 < 50% ,37. SensP value alone. To rule out false associations resulted from multiple tests, false-positive report probability (FPRP) analysis was also performed for all statistically significant findings as described previously [It has been acknowledged that many reported associations between genetic variation and susceptibility to diseases might be false positive, given determination of statistical significance largely relies on eviously –40. BrieP values were two-sided, and P<0.05 was considered as statistically significant finding.STATA  and SAS software  were used for statistical analyses. All NQO1 Pro187Ser and bladder cancer risk were identified from MEDLINE and EMBASE, and two additional publications from CBM (P<0.001) in controls [A total of 39 publications examining the association between from CBM . Initialcontrols . UltimatNQO1 exhibited significant increased risk for bladder cancer, when compared to non-carriers . Stratification analysis by ethnicity revealed a statistically significant association with bladder cancer risk among Asians , but not among Caucasian. When stratified by the source of control, an increased risk of bladder cancer was also suggested for variant alleles of NQO1 Pro187Ser polymorphism in the hospital-based subgroup , while no effect was observed in the population-based subgroup. When studies were stratified by the genotyping methods, we observed an increased bladder cancer risk among studies using PCR-RFLP method . We also found that there was a statistically significant association between increased risk and the SNP of interest  among studies with MAF>0.30. Additionally, we found that the risk of bladder cancer associated with NQO1 Pro187Ser polymorphism was pronounced and statistically significant among never smokers , but no association was detected when smokers were considered.As shown in NQO1 Pro187Ser polymorphism and bladder cancer risk may be due to the limited sample sizes, which need further validation in the studies with large sample size.The FPRP values for all statistically significant result are shown in NQO1 Pro187Ser polymorphism and bladder cancer risk . Therefore, the random-effects model was chosen since it generates wider CIs. Moreover, while the leave-one-out sensitivity analysis was performed, none of any single study altered the pooled ORs qualitatively (data not shown).Moderate heterogeneities were found for the studies assessing the association between P values were not statistical significant . In contrast, other covariates were not likely to cause heterogeneity across studies as indicated by P values: ethnicity , genotyping method , and MAF .With the purpose to find the source of heterogeneity, we also performed meta-regression by ethnicity, source of controls, genotyping methods and MAF. As shown in NQO1 Pro187Ser polymorphism and bladder cancer risk (data not shown).We performed both Begg’s and Egger’s tests to evaluate the publication bias for the studies included in the final meta-analysis . The shaNQO1 Pro187Ser polymorphism was associated with increased bladder cancer susceptibility. Further stratified analyses revealed that this association was more predominant among Asians, hospital-based studies, studies adopting PCR-RFLP method for genotyping, studies with MAF >0.30, as well as never smokers. Noteworthily, these results were further confirmed by FPRP analysis.In the current updated meta-analysis of 15 studies including a total of 4298 cases and 4275 controls, we found that the NQO1 Pro187Ser polymorphism in the bladder cancer risk [NQO1 Pro187Ser polymorphism.To our knowledge, several meta-analyses have been performed to investigate the role of cer risk –45. In acer risk , Chao etcer risk , Gao et cer risk , includicer risk . A meta-cer risk , 12 studcer risk , we did cer risk ,45. Howecer risk ,45, and cer risk . More imP value may sometime lead to false positive findings. To address this issue, FPRP analysis has been introduced, in which the observed P value coupled with both the prior probability and the statistical power of the test to validate the significance of a finding [To preclude the possibility that the findings may be false positive due to the limited sample size, FPRP analysis was performed in the current meta-analysis. The associations among all subjects, Asians, studies with hospital-based design, PCR-RFLP genotyping method, MAF >0.30, and never smokers were validated. It is well known that association studies solely depending on a  finding . Thus, i finding . TheoretNQO1 Pro187Ser polymorphism and bladder cancer risk, but the conclusions were controversial. Some studies reported that the Ser/Ser genotype of Pro187Ser polymorphism was significantly associated with increased bladder cancer risk, when Pro/Pro genotype was used as the reference group [NQO1 Pro187Ser polymorphism was shown to associate with bladder cancer in hospital-based subgroups but not population-based subgroups. Since the hospital-based subjects are usually less representative and more prone to bias than population-based studies, these results should be interpreted cautiously. We also found the never smokers harboring the variant genotype were associated with increased bladder cancer risk. The main reason may be ascribed to genetic susceptibility. In other words, low penetrance polymorphism, like NQO1 Pro187Ser, commonly only has weak effect on bladder cancer risk. Therefore, the effect of this SNP among smokers might be superseded by the much stronger effects of smoking. Other reasons for this positive association among never smokers could be the reduced sample sizes in the subgroups, and the fact that the never smokers may also be exposed to second-hand smoke and other risk factors. Furthermore, sensitivity analyses demonstrated that successively excluding one study at a time did not lead to obvious change in the pooled ORs, which strengthens the results of this meta-analysis. Meta-regression suggested that source of controls but not other covariates might partially explain the heterogeneity in the current meta-analysis. In addition, the absence of publication bias further supports the validity of our finding.NQO1 is an obligate two-electron reductase which can reduce reactive quinones to hydroquinones. Additionally, NQO1 also shows superoxide scavenging activity as well as protective activity against procarcinogenic benzenes, thus it has been considered as an important defense of host against cancer ,48. NQO1ce group ,21,24, wce group ,26, or uce group ,18,24. OSchistosoma hematobium infection status and other risk factors , which may lead some confounding bias. Second, the controls were not uniformly defined; some studies used healthy subjects as the control group, whereas others used cancer-free patients as the reference group. Third, sample size for each case-control study was relative small, with most studies including less than 500 cases, except for two [Though we have included the latest investigations, some limitations should be acknowledged, while interpreting the results. First, due to lack of original data, our conclusions were based on unadjusted estimates of ORs without adjustment for age, gender,  for two ,25. Ther for two . Meta-an for two . In thisNQO1 Pro187Ser polymorphism may confer host increased genetic susceptibility to the risk of bladder cancer. However, large and well-designed studies are warranted to validate our findings.In conclusion, the current meta-analysis indicates that the S1 Data(XLS)Click here for additional data file.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Table(DOC)Click here for additional data file.


Hyperuricemia has been reported to be associated with chronic kidney disease (CKD). However whether an elevated serum uric acid level is an independent risk factor for new-onset CKD remained controversial.A systematic review and meta-analysis using a literature search of online databases including PubMed, Embase, Ovid and ISI Web/Web of Science was conducted. Summary adjusted odds ratios with corresponding 95% confidence intervals (95% CI) were calculated to evaluate the risk estimates of hyperuricemia for new-onset CKD.Thirteen studies containing 190,718 participants were included. A significant positive association was found between elevated serum uric acid levels and new-onset CKD at follow-up . Hyperuricemia was found be an independent predictor for the development of newly diagnosed CKD in non-CKD patients . This association increased with increasing length of follow-up. No significant differences were found for risk estimates of the associations between elevated serum uric acid levels and developing CKD between males and females.With long-term follow-up of non-CKD individuals, elevated serum uric acid levels showed an increased risk for the development of chronic renal dysfunction. The prevalence of chronic kidney disease (CKD) is increasing in various populations worldwide, and risk factors associated with CKD have gained much attention in recent years . HyperteThe current meta-analysis was performed to quantitatively assess relationships between hyperuricemia and CKD, and also to evaluate whether associations were influenced by hypertension, hyperuricemia or other confounding factors, and whether they varied by study design, sex and geographical area.2 for more than 3 months or the presence of albuminuria (kidney damage) for more than 3 months, according to the National Kidney Foundation Kidney Disease Outcomes and Quality Initiative (KDOQI) CKD guidelines [A literature search was performed using electronic databases Medline Ovid/Medline (1948 to present), PubMed/Medline, Embase, and ISI Web/Web of Science for published studies from January 1970 to September 2013. Key words used were: “hyperuricemia”, “uric acid elevated”, “hyperuricaemia”, “uricacidemia”, and “uricacidaemia”; and “CKD” or “chronic kidney disease” or “chronic renal dysfunction” or “chronic renal insufficiency”. The “related items” function was used to broaden the search. The electronic search was up to September 2013 with no limitations regarding the type of publication. Studies were screened by two reviewers (L.L. and C.Y.) independently with the following inclusion criteria: (1) report of the association between serum uric acid (SUA) and new-onset CKD; (2) studies of observational cohort design; and (3) report of the hazard ratio (HR) or odds ratio (OR) in cohort studies with 95% confidence intervals (95% CI) or sufficient information to calculate these figures. Exclusion criteria were: (1) studies published in languages other than English; and (2) studies reporting on patients with end-stage renal disease or acute renal impairment or patients requiring dialysis. The definition of CKD was: eGFR <60 mL/min per 1.73 midelines . Studies2 with microalbuminuria or macroalbuminuria; Stage 2, GFR 60–89 mL/min per 1.73 m2 with microalbuminuria or macroalbuminuria; Stage 3, GFR 30–59 mL/min per 1.73 m2; and Stage 4 GFR 15–29 mL/min per 1.73 m2[KDOQI CKD guidelines were used for the definition of CKD severity: Stage 1, GFR >90 mL/min per 1.73 mr 1.73 m2. Two revThe Newcastle–Ottawa Scale (NOS) was used for meta-analysis of observational studies in epidemiology for assessment of quality . Risk ofχ2 test. P-values <0.05 were considered statistically significant.Statistical analysis was performed in accordance with The Cochrane Library handbook and the Quality of Reporting of Meta-Analyses guidelines ,15. DiffMeta-regression analysis was conducted to explore heterogeneity among studies. Possible sources of heterogeneity included participant-specific characteristics such as age, sex, location, and source of participants; and study-specific characteristics such as data type for calculating HR or OR (continuous variables or dichotomous variables), sample size, study quality, and definitions used for hyperuricemia. Funnel plots and Egger regression tests were used to investigate publication bias. We used RevMan version 5.1  and Stata version 11.0 for Windows  for data analysis and graph formation.We identified 1662 relevant citations in the combined search of online electronic databases  and 21 additional citations from the reference lists of relevant articles. After removing duplicated records, 790 studies were screened by examining titles and abstracts, and 129 relevant studies after primary selection were reviewed by reading the complete text for eligibility. There were 41 studies that reported on associations between SUA and renal disease, and these were assessed in detail. Articles with a cross-sectional or case–control style, a different definition of CKD or insufficient data were excluded. Finally, 13 studies that met inclusion criteria were included in our meta-analysis . Eleven studies defined CKD as the development of eGFR <60 mL/min per 1.73 mWith regard to choice of participants, 11 studies used population-based participants who underwent health examinations, while the source in the other two studies was hospital-based participants with diabetes mellitus ,24.Different cut-off levels were used for defining hyperuricemia Table . An SUA Adjustments made for potential confounders of at least three factors were mentioned in all 13 studies.Q = 34.76, P < 0.001, I2 = 83%)  with evidence of significant heterogeneity among studies    in a random effects model. Moderate heterogeneity was found among studies . For these five other studies, the association between hyperuricemia and the onset of CKD was still significantly positive .Results of meta-regression analysis indicated that heterogeneity was caused by follow-up year and sex proportion. One study from Japan only included male volunteers and had a follow-up of 18 years and reported a comparatively higher OR and contributed 44% of heterogeneity . After eResults of subgroup analysis according to sources of participants, geographical area, sex and follow-up year are shown in Table P = 0.07). Both groups showed significant independent associations between hyperuricemia and new-onset CKD.For subgroup analysis for source of participants, no differences were observed in summary OR for associations between hyperuricemia and CKD in patients with diabetes and the community-based population  and Western countries .et al. reported that a stronger association beween hyperuricemia and CKD for in females than males, a finding contrary to results from the other studies, contributed to the heterogeneity of pooled analysis [Three studies provided results for males and females, and the results of pooled analysis by sex indicated a similar significant positive association between hyperuricemia and new-onset CKD in both males  and females  . The Egger regression asymmetry test showed no significance for either SUA (P = 0.176) or hyperuricemia (P = 0.977).Funnel plots revealed no evidence of publication bias for associations between increasing SUA and new-onset CKD and the relationship between hyperuricemia and new-onset CKD Figure b. Resultet al. reported that uric acid level was independently associated with renal disease; however, the researchers included results from patients with end-stage renal disease or acute renal impairment and patients who received dialysis [et al. did not follow the KDOQI CKD guidelines [A previous meta-analysis conducted by Li dialysis . Additioidelines .et al. reported that the strength of the association between hyperuricemia and CKD was greater in males than in females [The present meta-analysis and systematic review found that elevated SUA was significantly positively associated with new-onset CKD in populations with normal renal function: individuals with hyperuricemia had an increased risk of new-onset CKD compared with those without hyperuricemia. Although the adjusted OR for the association between elevated SUA and the development of new-onset CKD was not great, it was found to be independent of sex, age, body mass index, alcohol intake, smoking, hypertension, metabolic syndrome, hypertriglyceridemia, diabetes and medication. In subgroup analysis, we found that the summary OR for the association between elevated SUA and development of new-onset CKD increased with increasing length of follow-up time, indicating hyperuricemia may play a role in the long-term progression of renal function. With regard to geographic distribution, subgroup analysis showed a stronger association between elevated SUA and CKD development in Western countries compared with Asian populations. This difference may be because of race, geographical or diet differences, as the Western diet might contain more purine-rich foods. Two studies by Chen and Xue  females ,31. Howeet al. suggested that treating hyperuricemia in adolescents with newly diagnosed hypertension was effective at lowering blood pressure, which indirectly decreased the risk of incidence of CKD [et al. revealed that allopurinol intervention in individuals with eGFR >60 mL/min/1.73 m2 significantly increased eGFR at follow-up [et al. reported that uric acid-lowering therapy with allopurinol could retard the progression of CKD, but had no effect on proteinuria and blood pressure [Our study is of significant clinical and public health importance. CKD is a very common disease and its prevalence is increasing in both developed and developing countries. Treating hyperuricemia may delay or even prevent the onset of CKD. Clinical studies conducted by Feig e of CKD . A case–ollow-up . A recenpressure . A signipressure .The present meta-analysis has potential limitations. First, observational cohort studies may have unknown confounding attribution bias and selection bias, which may distort the true effects. Second, OR or HR calculated using continuous and dichotomous variables were pooled to reduce heterogeneity. Some heterogeneity caused by different statistical methods is inevitable; for example, heterogeneity for pooled analysis in males was caused by one study using uric acid per SD for their calculations. Third, confounding variables are likely to be present. Hyperuricemia may also reflect an unhealthy lifestyle, such as smoking, obesity and hyperlipidemia. These risk factors have been confirmed to play a pathogenic role in diabetes, hypertension and metabolic syndrome, which also contribute to renal dysfunction. Half the studies examined did not make adjustments for metabolic syndrome and diabetes in their calculations. Fourth, heterogeneity of cumulative analysis, which may be caused by population source, follow-up year and gender, could only be partially explained by subgroup analysis on examining these factors. Subgroup analysis by race and different stages of CKD was not possible because of a lack of data. Finally, as the publication bias test was statistical, it is possible for publication bias to exist as the meta-analysis can only use the published studies.As with any observational study, associations do not imply causality. For example, in a recent Mendelian randomization analysis of two large cohorts, though estimates confirmed known observational associations between plasma uric acid and hyperuricemia with risk of ischemic heart disease, when using genotypic instruments for uric acid and hyperuricemia, the author saw no evidence for causal associations between uric acid and ischemic heart disease . Similaret al., uric acid induced phenotypic transition of cultured renal tubular cells, as epithelial-to-mesenchymal transition, which is a known mechanism for renal fibrosis [Traditionally, gout is associated with renal disease while hyperuricemia results in intraluminal crystals in collecting ducts of nephrons . Uric acfibrosis .We found that hyperuricemia could be a risk factor for CKD. For patients with subclinical kidney disease, hyperuricemia can be the consequence of decreased renal uric acid excretion, which could in turn further exacerbate kidney function. Therefore, the causal relationship between hyperuricemia and CKD is far more complicated than a simple cause-and-effect relationship. This means that the results of the current study should be interpreted with caution.Regardless of whether elevated SUA is solely a marker of subclinical chronic renal dysfunction or an independent risk factor for the development of CKD, careful attention is warranted. Our study emphasizes the need to identify individuals with hyperuricemia, as early intervention that decreases SUA levels may lower the risk of developing CKD. Randomized controlled studies of high quality are required to investigate the effects of decreasing uric acid levels in CKD patients and in individuals at high risk of developing CKD.This systematic review and meta-analysis demonstrated that, in the long-term follow-up of non-CKD individuals, elevated SUA levels showed an increased risk of developing chronic renal dysfunction.CKD: Chronic kidney disease; KDOQI: National kidney foundation kidney disease outcomes and quality initiative; NOS: Newcastle–ottawa scale.The authors declare that they have no competing interests.PF conceived the study and participated in its design. LL and CY participated in the design of the study and performed statistical analyses. The manuscript was prepared by LL, CY, YZ, XZ, FL and PF. All authors participated in discussions about the manuscript and approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/15/122/prepubThe MOOSE Checklist of the article.Click here for fileThe NOS quality assessment of the included cohort studies.Click here for file


Cyclin D1 (CCND1) is critical in the transition of the cell cycle from the G1 to S phases, and unbalanced cell cycle regulation is a hallmark of carcinogenesis. Numerous epidemiological studies have evaluated the association between the CCND1 A870G polymorphism and the risk of prostate cancer (PCa). However, these studies have yielded conflicting results.In the present study, the possible association above was assessed by a meta-analysis. Eligible articles were identified for the period up to July 2014. Pooled odds ratios (ORs) with 95% confidence intervals (95% CI) were appropriately derived from fixed effects or random effects models.P = 0.380; OR = 1.088, 95% CI = 0.896 to 1.321 for AA versus GG, P = 0.393; OR = 1.044, 95% CI = 0.941 to 1.158 for GA versus GG, P = 0.414; OR = 1.053, 95% CI = 0.955 to 1.161 for the dominant model AA + GA versus GG, P = 0.303; OR = 1.072, 95% CI = 0.881 to 1.306 for the recessive model AA versus AA + GA, P = 0.486). Moreover, subgroup analyses according to ethnicity failed to demonstrate a significant association between this polymorphism and prostate cancer. In addition, we also performed a stratified analysis of cases with PCa metastasis, and the results supported the findings of no significant association between CCND1 A870G polymorphism and metastasis risk of PCa.A total of ten case-control studies, which included 3,820 cases and 3,825 controls, were identified. Overall, the allelic/genotypic association between the G870A polymorphism and prostate cancer was nonsignificant (OR = 1.045, 95% CI = 0.947 to 1.153 for A versus G, Our results suggest that the CCND1 A870G polymorphism might not be a potential candidate for predicting prostate cancer risk, including metastasis risk. As one of the most frequent malignant diseases among men, prostate cancer (PCa) is a complex disease that is caused by a multitude of factors . RecentlCyclin D1 mRNA is alternatively spliced to transcribe two different transcripts, which yield to functionally different proteins [CCND1 is involved, alternatively, in splicing of CCND mRNA [Cell cycle dysregulation plays a critical role in a variety of malignancies and contributes to an increased risk of metastasis, in part, by altering the cell’s ability to respond appropriately to DNA damage ,5. A numproteins ,16, and CND mRNA .CCND1 A/A genotype and the risk of various cancers. Qin et al. found that the CCND1 A/A genotype may increase brain tumor risk, especially for gliomas [et al. also reported that an A870G polymorphism in CCND1 confers an increased risk for breast cancer [et al. revealed that a CCND1 G870A polymorphism has no association with esophageal cancer risk in ethnicity and histology [CCND1 A870G polymorphism and prostate cancer susceptibility, the conclusions have been inconsistent. Wang et al. reported that the A allele of the CCND1 A870G polymorphism was recessively associated with susceptibility to PCa [CCND1 A870G polymorphism and prostate cancer was found by Chen et al. [Epidemiological studies have reported the association between the  gliomas . Yang ett cancer . Howeveristology . Althougy to PCa . But no n et al. .CCND1 A870G polymorphism and prostate cancer risk, which were previously published, were analyzed via a meta-analysis to examine a more specific association between the CCND1 A870G polymorphism and prostate cancer risk and various published observational studies.In the present study, ten case-control studies on the CCND1/cyclin D1, prostate cancer/carcinoma/tumor, variant/genotype/polymorphism/SNP, and the combined phrases for all genetic studies on the association between the CCND1 A870G polymorphism and prostate cancer risk. We also checked the references of the retrieved studies and reviews to ensure the complement of this meta-analysis. This work was approved by the ethics committees of Zhejiang Provincial People’s Hospital.The PubMed, MEDLIN, and Web of Science databases were searched for studies published before July 2014. The key words used for searching were as follows: CCND1 polymorphism and prostate cancer risk, and (c) sufficient published data for both patients and controls.The following inclusion criteria were used for the literature selection in our meta-analysis: (a) case-control study, (b) evaluation of the The following exclusion criteria were set: (1) incomplete raw data, (2) repetitive reports , (3) materials and methods were not well-described and reliable, or (4) not an English paper.Two investigators extracted information independently according to the inclusion and exclusion criteria listed. When it came to conflicting evaluations, an agreement was reached after a discussion. For each eligible study, we collected information as follows: the first author’s name, publication data, country of origin, sources of controls, number of different genotypes, and ethnicity of the study population (categorized as Asian and Caucasian). For studies including subjects of different ethnic groups, data were extracted separately for each ethnic group whenever possible.χ2 of Fisher’s exact test). Heterogeneity and cumulative analysis were assessed by χ2-based Q test. OR estimation was calculated with the fixed effect model (Mantel-Haenszel method) when statistical heterogeneity did not exist (P > 0.10). Otherwise, the random effects model (DerSimonian and Laird method) was selected. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between the CCND1 polymorphism and prostate cancer risk. The pooled ORs were performed for a codominant model (GA versus GG and AA versus GG), dominant model (GA/AA versus GG), and recessive model (AA versus GA/GG). Stratified analyses were also performed by ethnicity. Publication bias was evaluated by Funnel plots, and Begg’s test and Egger’s test were also used to detect publication bias. Statistical analysis was performed using STATA versions 11.0 .The Hardy-Weinberg equilibrium (HWE) for the control group of each study was assessed using a goodness-of-fit test (P > 0.05) in studies except for Mandal et al. (P = 0.013) and Koike et al. (P = 0.004).After an extensive search, a total of 43 relevant studies were identified Figure . FollowiCCND1 A870G polymorphism and prostate cancer risk. The combined results based on all studies revealed that variant genotypes are not associated with increased prostate cancer risk in different genetic models  , and the random effects model was employed in these studies. We did not find significant heterogeneity for the following model , and a fixed effects model was performed.The following genetic model of the ten studies showed statistically significant heterogeneity using the CCND1 G720A polymorphism . This result was confirmed by the Begg’s rank correlation method  , which increased the frequency of alternative splicing and encoded a protein with an altered C-terminal domain and increased the stability or half-life of the protein, has garnered wide attention. To date, several studies have reported the role of the CCND1 G870A polymorphism in prostate cancer risk [CCND1 G870A polymorphism associated with prostate cancer, we conducted a meta-analysis of results from ten case-control studies on the association of the CCND1 G870A polymorphism with PCa risk. Overall, a total of 3,820 cases and 3,825 controls were included. However, the results indicated that no significant association between the CCND1 A870G polymorphism and PCa risk was found.Cell cycle regulation plays an important role in the evolution of cancer by influencing cell proliferation, differentiation, and apoptosis . CCND1, cer risk ,22,24. Bet al. [CCND1 A allele was more frequently observed in the PCa group than the control group, and men with the AA genotype had an increased risk of PCa compared to those with the GG genotype. Mandal et al. [CCND1 AA genotype was observed to be associated with a significant increase in PCa risk. However, Koike et al. found that no significant association of the genotype frequency of the CCND1 with overall cases and controls [CCND1 A870G polymorphism and PCa risk was found.Wang et al.  showed tl et al.  also revcontrols . Our preCCND1 A allele showed significantly increased risk of PCa metastasis [et al. did not find any significant risk when analyzing data for the risk of susceptibility for metastasis with the CCND1 polymorphism [CCND1 A870G polymorphism and metastasis risk of PCa, as reported by Mandal et al. [et al. [CCND1 A870G polymorphism might be in close linkage with different nearby causal variants in one ethnic population but not in another, according to the report of Yu et al. [Stratification analysis showed that the tastasis . But Manmorphism . In our l et al. . But the [et al. . Base on [et al. . Differeu et al. . In addiCCND1 A870G polymorphism and did not evaluate other genes or polymorphisms; whether this polymorphism integrated with other risk factors to enhance the predictive power requires further study.However, some limitations of this meta-analysis should be addressed. First, the results were based on the unadjusted estimates with original data from these collected studies being unavailable, which limited the evaluation with certain covariates, including cancer type, smoking, drinking, age, and other environmental factors. Second, the controls of several studies were various in the analysis, which may have induced the bias of the results and prevented the drawing of more detailed conclusions. Third, the single-locus-based nature of this meta-analysis precluded the possibility of gene-gene and gene-environment interactions; the analysis did not consider these factors because of the lack of sufficient data. Furthermore, we only concentrated on the CCND1 A870G and prostate cancer susceptibility. In addition, our observations raise the question of a potential heterogeneous effect of A870G across different ethnic populations. Nevertheless, for practical reasons, we hope that additional studies of CCND1 that include functional DNA repair gene polymorphisms in a large cohort of different ethnicities, combined with more appropriate methods, will augment the etiology of the pathogenesis of PCa.In conclusion, we expanded previous individually underpowered studies and suggested that no obvious association was found between the


SELE gene polymorphisms (A516C and G98T) and CAD susceptibility. We therefore chose to perform a meta-analysis to determine the association.Published genetic association studies have produced controversial results regarding the association of Twenty-seven eligible articles were identified through electronic databases, providing 5170 CAD cases and 4996 controls. Fixed-effects or random-effects summary ORs were calculated to estimate the risk of CAD in relation to A516C and G98T. Forest plots and funnel plots were constructed by Stata software 12.0.A strong association was observed between A516C and susceptibility of CAD among 4757 cases and 4272 controls. The summary OR was greatest in individuals carrying the CC genotype . A significantly increased risk was indicated in both Caucasians and Asians. The analyses by disease type showed a significant increase in the risk of AP and MI. We also noted a strong association in population-based studies. In the analyses of G98T, data were available for 1422 cases and 1625 controls. We saw a markedly increased risk of CAD associated with G98T. The highest risk was indicated in individuals with the TT genotype . A similar trend was seen in Asians and population-based studies.SELE gene may be associated with increased susceptibility of CAD.These findings provide consistent evidence that A516C and G98T polymorphisms of the  Despite the significantly declined global mortality, the occurrence rate remains especially high in developed countries.2 CAD is a multifactorial disease. Multiple traditional risk factors have been identified, but they can only explain a small fraction of reported cases.10 Thus, there must be other causes. Recently, much attention has been given to the hypothesis that CAD is a consequence of the inheritance of high- or low-penetrance genes involved in inflammation processes.12Coronary artery disease (CAD) has become one of the major causes of death worldwide.15The selectins are a class of cell adhesion molecules involved in chronic and acute inflammation processes. These single-chain transmembrane glycoproteins are expressed on endothelial cells after stimulation by inflammatory cytokines. The expression profile of selectins on the vascular wall is a determinant for the adhesion of pathological cells to endothelium, as the presence of endothelial selectins facilitates the adhesion. Accumulative data have implicated a linkage between selectins and the occurrence of CAD.SELE gene is located at chromosome 1q22-q25 and contains 14 exons. Genetic polymorphisms at the SELE locus may upregulate the gene expression levels, and thus influence the biological functions of their protein.16 There is a A to C single nucleotide change at position 561 . The common polymorphism lies in the epidermal growth factor-like domain of the SELE gene and results in arginine to serine (Ser128Arg) amino acid substitution at codon 128. Another polymorphism is a G to T nucleotide change in the 5’-untranslated region . Several lines of evidence have demonstrated significantly higher plasma SELE levels attributable to A561C and G98T polymorphisms.55 However, previous studies differ widely in their conclusions on the association between the SELE gene polymorphisms and CAD risk. In order to better define the association, we performed a meta-analysis incorporating 27 articles with 5170 CAD cases and 4996 controls.E-selectin (SELE) is expressed on activated endothelial cells and plays a key role in the binding of circulating lymphocytes and monocytes to endothelial cells. The SELE, polymorphism and coronary artery disease, and their synonyms . Additional usable records were identified by scanning the reference lists of related original articles, narrative reviews, and meta-analyses. This study was approved by the ethic committee of Second Clinical Medical College of Jinan University, Shenzhen People's Hospital.Electronic databases of PubMed, ISI Web of Science, China Wanfang Database, and China National Knowledge Infrastructure (CNKI) were searched to seek all potentially relevant records written in English or Chinese language. We combined the following keywords:Eligible studies were selected based on the predefined criteria. If several papers were conducted on the same CAD patients, the largest paper with complete data was considered eligible for inclusion.Had a case-control/cohort design;SELE polymorphisms and CAD susceptibility;Evaluated the hypothesis that there was an association between Provided sufficient data to estimate odds ratios (ORs) with 95% confidence intervals (95% CIs);Included human subjects.Inclusion CriteriaPublished as an abstract or related forms of summary;Reported too limited data to calculate the ORs;Only patients were included;Review articles and meta-analyses.Exclusion criteriaFor the studies finally included in the meta-analysis, data on the following items were extracted by 2 independent reviewers: study design, total cases, and controls, first author, publication year, location of study, ethnicity, source of controls, disease type, diagnosis of cases, genotype numbers, and methods applied to determine the genotypes of A561C and G98T polymorphisms. Discrepancies were resolved through discussion including a third reviewer.SELE polymorphisms. Inter-study heterogeneity was detected with the χ2-based Q test, and P value less than 0.05 represented presence of heterogeneity. We calculated random-effects summary ORs using the DerSimonian and Laird method when the Q test indicated significant heterogeneity (P < 0.05); otherwise, we estimated fixed-effects summary ORs using the Mantel–Haenszel method. Hardy–Weinberg equilibrium deviation was evaluated by Fisher exact test among controls. Begg's funnel plot and Egger's linear regression test were performed to evaluate publication bias.18 Subgroup analyses were conducted by several characteristics  to assess the association for each subgroup. In addition, we performed sensitivity analyses to identify the studies that exerted significant influence on summary ORs.Statistical data were done using Stata software . Summary ORs were calculated to estimate the strength of association between CAD risk and 45Figure The literature search according to inclusion and exclusion criteria yielded 102 records. Of these, 97 were retained after exclusion of duplicates. The review of title, abstract, and full text when necessary helped to exclude 70 more records. Thus, 27 articles on A561C and/or G98T polymorphisms and CAD were ultimately included in our analysis.In the meta-analysis of A561C polymorphism and CAD risk, data were available for 4757 cases and 4272 controls included in 24 articles. As shown in Table In the subgroup analyses by ethnicity, we noted a strong association for Caucasians and Asians Figure . Final aMeta-analysis of G98T polymorphism and CAD risk was based on 1422 cases and 1625 controls combined from 10 articles. We observed a strong association in all models tested with the exception of GT versus GG. The OR was greatest in TT versus GT/GG model  and relatively lower in T versus G model . In order to identify the outliers, we performed sensitivity analyses. The results were homogeneous when 2 studies, published by Jiang et al and Morgan et al32,44, respectively, were removed (P > 0.05). Although no significant heterogeneity was indicated in the analyses of G98T polymorphism, we also conducted sensitivity analyses to examine the stability of each risk estimate. The results suggested no substantial influence on the pooled ORs (data not shown).Several analyses of A561C polymorphism demonstrated presence of heterogeneity between studies (P > 0.05). However, Egger's test suggested evidence of significant publication bias in CA versus AA model of A561C polymorphism, and in GT versus TT model of G98T polymorphism (P < 0.05). The funnel plots are shown in Figures The circles, corresponding to the single studies, were symmetrically distributed in the funnel plots created for A561C and G98T polymorphisms . These findings are biologically plausible, as single nucleotide polymorphisms at the SELE locus affect normal functions of the gene by upregulating the gene expression levels.53 The observation of upregulated expression levels of the SELE gene due to polymorphisms is supported by Bannan et al, who found significantly higher levels associated with the C allele at the A561C polymorphism.54 A more recent study by Mlekusch et al lend further support for the significant association between increased plasma SELE levels and the SELE gene polymorphisms.55In our meta-analysis, genotype data were available for a total of 5170 CAD cases and 4996 controls pooled from 27 published papers. We provided some evidence that seemed to support a strong association between SELE gene polymorphisms with CAD risk.56 However, they did not analyze the risk of several disease types, such as AP and MI. In our study, we found a strong association between A561C polymorphism and the risk of AP and MI. The second meta-analysis was published by Dong et al.57 A total of 3193 CAD cases and 3233 control subjects were pooled from 20 case-control studies. Unlike the first meta-analysis, Dong et al did not demonstrate a positive association for Caucasians and MI. These observations were not consistent with the present study where more than 3500 subjects (1977 cases and 1763 controls) were included compared with the second analysis. In the most recent analysis, Wu et al only identified 10 studies with 3369 cases and 2577 controls for the A561C polymorphism,15 and found an increased risk for Asians, but not for Caucasians. Unlike the 2 more recent analyses, our analysis in which 1464 more subjects of Caucasian origin were combined even compared with the larger study, indicated a significantly higher risk of CAD associated with the C allele at A561C polymorphism. Therefore, the failure to include all informative studies may have biased some conclusions of the previous meta-analyses.We identified 3 published meta-analyses evaluating the risk of CAD in relation to the A561C polymorphism and/or the G98T polymorphism. In the first meta-analysis, Wang et al identified 24 articles, 3 articles less than our analysis, showing a significant association of the 2 Certain limitations need to be noted in explanation of the present findings. First, although we have identified all published papers, they total sample is still relatively small and remains to be expanded to validate the positive associations suggested in the current study. Second, Egger's test showed evidence of significant publication bias that may be caused by the inclusion of several small studies. In addition, there was large inter-study heterogeneity in the results of some analyses. Possible causes include heterogeneous experimental designs, different subject populations, interventions, and choice of analysis. Third, CAD is a heterogeneous disease. Both environmental and genetic factors could contribute to the malignant development. But additional analyses to detect the effects of gene-environment interactions were not allowed because of lack of related data.SELE locus with higher risk of CAD. This study may help to better understand the biological mechanism underlying the pathology of CAD, and this might ultimately facilitate earlier diagnosis, improved prevention and treatment. The role of SELE gene polymorphisms in the etiology of CAD remains to be elucidated in a larger study.In conclusion, our data suggested a significant association of the A561C and G98T polymorphisms at the


Research has indicated that the rs12203592 and rs872071 interferon regulatory factor 4 (IRF4) gene polymorphisms correlate with the risk of cancer, especially skin cancer and haematological malignancies, but the results remain controversial. To understand better the effects of these two polymorphisms on skin cancer and haematological malignancies susceptibility, a cumulative meta-analysis was performed.We conducted a search using the PubMed and Web of Science databases for relevant case-control studies published before April 2014. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using fixed- or random-effects models where appropriate. Heterogeneity test, publication bias test, and sensitivity analysis were also performed.In total, 11 articles comprised of 19 case–control studies were identified; five focused on the rs12203592 polymorphism with 7,992 cases and 8,849 controls, and six were on the rs872071 polymorphism with 3108 cases and 8300 controls. As for rs12203592, a significant correlation with overall skin cancer and haematological malignancies risk was found with the homozygote comparison model  and recessive model . For rs872071, a significantly elevated haematological malignancies risk was observed in all genetic models . Similarly, increased skin cancer and haematological malignancies risk was also identified after stratification of the SNP data by cancer type, ethnicity and source of controls for both polymorphisms.Our meta-analysis indicated that the rs12203592 and rs872071 IRF4 gene polymorphisms are associated with individual susceptibility to skin cancer and haematological malignancies. Moreover, the effect of the rs12203592 polymorphism on skin cancer risk was particularly prominent among Caucasians. Further functional research should be performed to validate the association. Cancer is a multifactorial disease resulting from complex interactions between environmental and genetic factors. Cancer is one of the leading causes of death worldwide ,2. Skin Haematological malignancies, including leukaemia, lymphoma and plasma cell dyscrasia, are a group of disorders that affect blood, bone marrow, lymph nodes and spleen. These malignancies make up approximately 9.5% of all new cancer diagnoses in the United States ,9. HaemaInterferon regulatory factors (IRF) are a family of transcription factors characterised by a DNA-binding domain containing a five-tryptophan residue repeat ,16. IRFsGenome-wide association studies (GWAS) are the ideal strategy to select common, low-penetrance susceptibility loci without prior hypotheses about the role of the genes in disease development. Recent GWAS have reported that variants at several sites within the IRF4 gene may be implicated in the risk of cancer. Most importantly, the intron 4 SNP rs12203592 and 3′ UTR SNP rs872071 are associated with an increased risk for melanoma, BCC ,26, CLL We searched the PubMed and Web of Science databases for all relevant articles regarding IRF4 SNPs associated with cancer risk . The following keywords were used: “IRF4” or “interferon regulatory factor 4”, “polymorphisms or variant or SNP or mutation” and “cancer or tumor or neoplasm or carcinoma”. The search was conducted exclusively on human subjects. The reference lists of reviews and retrieved articles were simultaneously hand-searched. We did not consider abstracts or unpublished reports.All abstracts of citations and retrieved studies were reviewed. The following criteria were used to identify eligible published studies: (i) the study evaluated the association between the IRF4 polymorphisms (rs12203592 and rs872071) and cancer risk; (ii) the publication was a case–control or case-cohort study; (iii) the paper provided sample size, distribution of alleles, genotypes or other information that can help us estimate an OR with 95% confidence interval (95% CI); (iv) the genotype distribution of the control population is consistent with Hardy-Weinberg Equilibrium (HWE). Accordingly, publications were excluded using the following criteria: (i) articles that were not about cancer research; (ii) the publication contained duplicated previous research; (iii) the study did not include usable genotype data were excluded.Two investigators independently extracted information from all eligible publications according to the inclusion criteria listed above. The results were compared, and disagreements were resolved by discussion until a consensus was reached. Data extracted from each study included the following characteristics: the first author’s name, the year of publication, the country of participants, ethnicity, cancer type, source of control group , and the genotype frequency of the rs12203592 and rs872071 polymorphism in the cases and controls.All statistical analysis was performed using STATA software . Two sided P-values < 0.05 were considered statistically significant. Our meta-analysis recalculated HWE in the controls for each study. The goodness of fit test (chi-square or Fisher’s exact test) was used to assess deviation from HWE (significant at the 0.05 level). Studies that deviated from HWE were removed.ORs with 95% CIs were used to estimate the strength of the association between the IRF4 rs12203592 and rs872071 polymorphisms and skin cancer and haematopoietic malignancies risk. In addition, the Z-test was also used, and a P value < 0.05 indicated statistical significance for the association. We examined the association between the rs12203592 IRF4 polymorphism and skin cancer and haematopoietic malignancies using the homozygote comparison (TT versus CC), heterozygote comparison (CT versus CC), dominant genetic model (TT + CT versus CC), recessive genetic model (TT versus CT + CC) and additive genetic model (T versus C). The same methods were applied to the analysis of the rs872071 IRF4 polymorphism. In addition, a stratified analysis was also performed based on cancer type, ethnicity and the source of controls.I2 test. I2 values of 25, 50, and 75% were indicative of low, moderate, and high heterogeneity, respectively.The assumption of heterogeneity was ascertained using a chi-based Q-test. A P-value less than 0.05 for the Q test indicated significant heterogeneity among the studies. The pooled OR was estimated using a fixed- or random-effects model, where appropriate. If the P value was less than 0.05 indicative of heterogeneity across studies, a random-effects model (DerSimonian and Laird) was utilised for the meta-analysis . OtherwiThe sensitivity analysis was conducted by removing one study at a time to evaluate the quality and consistency of the meta-analysis results. Publication bias was qualitatively and quantitatively assessed using the Begg’s funnel plots and Egger’s test, respectively . To ensuA total of 179 potential individual publications were initially identified after a systematic literature search of the PubMed, Embase and Web of Science databases. The titles, abstracts and full texts of the retrieved articles were reviewed based on the inclusion criteria shown in Figure A summary of the meta-analysis findings on the association between the rs12203592 and rs872071 IRF4 polymorphisms and skin cancer and haematopoietic malignancies risk is presented in Table With respect to the rs872071 polymorphism, a total of 8 studies from 6 articles were included. Of the 8 eligible studies, 4 focused exclusively on CLL, 3 on lymphoma and 1 on MM. Caucasian populations were used in 6 studies, and Asians were assessed in 2. Five of the studies were population-based controls, and 3 used hospital-based controls. Overall, a significantly elevated haematological malignancies risk was associated with the rs872071 polymorphism in all genetic models . After subgroup analysis by cancer type, the heterogeneity effectively disappeared in the CLL subgroup and lymphoma subgroup. In the analysis of ethnicity, the heterogeneity was significantly removed in the Asian population but remained in the Caucasians. When stratified based on the source of controls, heterogeneity was not observed in the hospital-based control subgroups. The heterogeneity values are presented in Table Publication biases of the literature were investigated using the Begg’s funnel plot and Egger’s test. With respect to the rs12203592 polymorphism, the results of the Begg’s funnel plot suggested no publication bias. The Egger’s test did not show statistical evidence for publication bias . The shapes of the funnel plots did not reveal any evidence of obvious asymmetry for the rs872071 polymorphism with all genetic models . Similarly, the results of the Egger’s test indicated a lack of publication bias .Sensitivity analyses were also performed in the current meta-analysis to assess the influence of each individual study on the pooled ORs by sequential removal of individual studies. For both the rs12203592 and rs872071 polymorphisms in the IRF4 gene, the results suggested that no individual study significantly altered the pooled results, thereby suggesting that the results of this meta-analysis are robust and reliable  from frequency distributions reported in the original publications, so our analyses are not adjusted for the main risk factors of both skin cancer and haematological malignancies. In addition, cancer is a complex disease with a multifactorial aetiology. Lack of original data for gene-gene and gene-environment interactions limited our further evaluation. Despite these limitations, the advantages of our meta-analysis should also be noted. First, studies that satisfactorily met our selection criteria were included in the present meta-analysis. The substantial number of cases and controls pooled from the different studies significantly increased the statistical power of the analysis. Second, the distribution of genotypes in the controls was in agreement with Hardy-Weinberg equilibrium (P > 0.05) for all studies. Third, the results of the Funnel plot and Egger’s test detected no publication bias, indicating that the pooled result is reliable.The evidence from the present meta-analysis supports the notion that both the rs12203592 and rs872071 IRF4 gene polymorphisms are associated with an individual’s susceptibility to skin cancer and haematological malignancies. The effect of the rs12203592 polymorphism on cancer is particularly prominent among Caucasians; however, no significant association with cancer risk was demonstrated in the NHL subgroup. Based on the limitations of the present study listed above, further functional studies between these polymorphisms and cancer risk are warranted.IRF4: Interferon regulatory factor 4; HL: Hodgkin lymphoma; NHL: Non-Hodgkin lymphoma; MM: Multiple myeloma; CLL: Chronic lymphocytic leukaemia; BCC: Basal cell carcinoma; SCC: Squamous cell carcinoma; PB: Population based; HB: Hospital based; OR: Odd ratio; CI: Confidence interval.The authors declare that they are no competing interests.SW, QY participated in collection of data and manuscript preparation. SW, QY and PC performed the statistical analysis. AG, PZ, PC participated in study design and critically revised the manuscript. AG and PZ participated in study design and manuscript preparation. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/410/prepub