Recently, researchers in a number of studies have explored the association between the Toll-like receptor 2 (TLR2) Arg753Gln polymorphism and sepsis risk. However, the results were conflicting. In this meta-analysis, we aimed to confirm the effect of the TLR2 Arg753Gln polymorphism on sepsis risk.Relevant records up to 1 June 2015 were retrieved from the PubMed, Embase, and Web of Knowledge databases. The odds ratios with their corresponding 95 % confidence intervals were used to assess the association between the TLR2 Arg753Gln polymorphism and sepsis risk. The selection of a fixed or random effects model was made according to a heterogeneity test in total and subgroup analyses. Sensitivity analysis and publication bias test were performed to ensure the reliability of our results.A total of 12 studies with aggregate totals of 898 cases and 1517 controls met our inclusion criteria for meta-analysis. There were significant associations between the TLR2 Arg753Gln polymorphism and sepsis risk in overall analyses under two genetic models . In addition, subgroup analyses based on age group, ethnicity, sepsis type, and source of control also showed a significant effect of the TLR2 Arg753Gln polymorphism on sepsis risk.Our present meta-analysis supports a direct effect of the TLR2 Arg753Gln polymorphism on sepsis risk, especially in Europeans. The TLR2 Arg753Gln polymorphism might be used as a relevant risk estimate for the development of sepsis. Studies with larger sample sizes and homogeneous groups of patients with sepsis are required for further analysis.The online version of this article (doi:10.1186/s13054-015-1130-3) contains supplementary material, which is available to authorized users. Sepsis is a complex clinical syndrome that results from a systemic inflammatory response to bacteria and/or bacterial products . It remaStaphylococcus aureus sepsis [TLR2 may be an appealing candidate gene for determining sepsis risk.TLRs, which are a group of pattern recognition receptors, are composed of ten transmembrane proteins in humans  and are s sepsis . This evTLR2 gene, mapped to chromosome 4q32, consists of three exons. Population-based case–control studies have shown that the polymorphisms of TLR2 could influence poor outcomes in a number of diseases, such as cancer, tuberculosis, and infective endocarditis [The carditis –19. Amoncarditis . RecentlWe searched all published articles in the PubMed, Embase, and Web of Knowledge databases up to 1 June 2015. The keywords used were as follows: “Toll-like receptor 2” or “TLR2”; “sepsis” “septic shock,” or “severe sepsis”; and “polymorphism,” “variation,” “mutation,” or “genotype.” Relevant studies were retrieved, and their references were checked to assess other relevant publications. Authors were contacted to obtain related data not revealed in the original articles.The inclusion criteria were as follows: (1) the study had to include an evaluation of the association between the TLR2 Arg753Gln polymorphism and sepsis risk; (2) the study design had to be a case–control or cohort study; and (3) the number of the study population genotypes had to be stated in the article or obtained by contacting the authors. The exclusion criteria were as follows: (1) study with insufficient number of population genotype; (2) review, comment, or abstract; and (3) no mutation in the study population. When an article reported results on subjects of different ethnicities, we treated each ethnicity as a separate study.Two investigators independently screened titles, abstracts, and full text of the articles to reduce errors and ensure the reliability of the results. A standardized extraction form was used for information collection. Disagreement was resolved by discussion. Information collected from the selected studies include the first author’s name, publication year, country in which the study was done, subjects’ ethnicities, subjects’ age groups, sepsis types, source of control subjects, and genotype numbers in cases and control subjects for each TLR2 Arg753Gln genotype. Hardy-Weinberg equilibrium (HWE) was tested based on the collected data.I2 value and a χ2-based Q test. P > 0.10 for the Q test and I2 values less than 50 % revealed no obvious heterogeneity across studies, allowing us to use a fixed effects model (the Mantel-Haenszel method); otherwise, a random effects model (the DerSimonian and Laird method) was selected. Galbraith plots were used to investigate the source of between-study heterogeneity. Sensitivity analysis was performed by sequentially removing individual studies to assess the reliability of our results. Publication bias was examined by Begg’s funnel plot qualitatively  and Egger’s test quantitatively. All statistical analyses were performed using RevMan 5.2 software  and STATA 12.0 software .We performed our meta-analysis under the allele comparison model (A vs. B) and the dominant model (AB/AA vs. BB) for the unknown inherited model of sepsis. Because of the lack of a mutant homozygote for the TLR2 Arg753Gln polymorphism, we could not conduct the related analysis under other inherited models. Odds ratios (ORs) with their 95 % confidence intervals (CIs) were used to assess the association between the TLR2 Arg753Gln polymorphism and sepsis risk. The Z-test was selected to evaluate the statistical significance of pooled ORs. In addition to total comparisons, stratified analyses based on age group, ethnicity, sepsis type, and source of control subjects were also carried out. Heterogeneity across studies was evaluated with the A total of 247 records were identified by using different combinations of search terms in PubMed, Embase, and Web of Knowledge, and 1 record was identified by checking reference lists. After excluding 70 duplications, 149 records were removed for their unmatched titles or abstracts. Full-text reading helped us to remove 18 records . The author of record with insufficient genotype data was contacted. However, no answer was received. Ultimately, 12 studies (11 records) –31 were Of the 12 included studies, 9 were conducted with Europeans, 1 in an Asian Han population, 1 in an African population, and 1 in a mixed ethnicities population. Seven studies were about sepsis, one was on severe sepsis, and one was about septic shock. In addition, the study populations in our included studies consisted of adults (nine studies) and children (three studies). Five studies used critically ill patients and another five used healthy populations as control subjects. All of the studies were consistent with HWE, except for the study conducted by Lee et al. . The chaP = 0.03; for AA/GA vs. GG, OR 1.92, 95 % CI 1.11–3.32, P = 0.02)  with 898 cases and 1517 controls were examined to determine the association between the TLR2 Arg753Gln polymorphism and sepsis risk –31. The P = 0.01) and the dominant model (P = 0.01), respectively. Subgroup analyses were performed to ensure the homogeneity of study populations. However, the between-study heterogeneity did not decrease substantially, except in adult and critically ill patient subgroup analyses. A Galbraith plot was selected to explore the source of heterogeneity for total analyses. The studies conducted by Lee et al. [P = 0.21, I2 = 25 %). The association between the TLR2 Arg753Gln polymorphism and sepsis risk changed little  . There was a significant association between the TLR2 Arg753Gln polymorphism and sepsis risk   and the dominant model quantitatively (P = 0.590).Publication bias within each study might not represent all studies. Therefore, Egger’s test and Begg’s funnel plot were used to evaluate publication bias quantitatively and qualitatively, respectively. Although slightly asymmetrical funnel plots were found in our results Fig. , Egger’sSepsis is a complex clinical syndrome that results from a systemic inflammatory response to bacteria and/or bacterial products. Previous studies have shown that the innate immune system is an essential part of sepsis development and progression , 32, 33.To the best of our knowledge, this is the first meta-analysis in which the relationship between TLR2 polymorphism and sepsis risk has been explored. We found significant associations between the TLR2 Arg753Gln polymorphism and sepsis risk in two genetic models . In addition, subgroup analyses based on age group, ethnicity, sepsis type, and source of control subjects were performed. We noted that the TLR2 Arg753Gln polymorphism was also significantly associated with sepsis risk in adult, European, sepsis, and critically ill patient subgroups. These results further proved the important role of the TLR2 Arg753Gln polymorphism in the development of sepsis. Since there were fewer than three studies performed in other subgroups, analyses of other subgroups were not conducted; more studies are required to analyze these conditions.Our meta-analysis included a study with patients taking immune-suppressive medications after liver transplant, and the results also were not inconsistent with HWE. After we removed that study from the overall analysis, the results changed little. These patients may not have influenced our results, and more patients taking immune-suppressive medications are needed to explore this association. Some researchers stated that they believe that pediatric patients may be more sensitive than adult patients to sepsis risk factors. However, there was no significant association between the TLR2 Arg753Gln polymorphism and susceptibility to sepsis in our pediatric subgroup analysis. This finding may be due to a relatively small sample size in our meta-analysis. In addition, we found that only one study was performed in an Asian population in our meta-analysis. More studies in Asian populations are needed to estimate the effect of the TLR2 Arg753Gln polymorphism on sepsis risk.To better ensure the reliability of our results, we also explored the source of between-study heterogeneity in our meta-analysis. Obvious between-study heterogeneity was found in both total and subgroup analyses. Galbraith plots indicated that the studies conducted by Lee et al.  and TellTLR2 gene. A gene function study indicated that the TLR2 Arg753Gln polymorphism could impair tyrosine phosphorylation, dimerization with TLR6, and MyD88 recruitment with an effect on nuclear factor κB activation [How might the TLR2 Arg753Gln polymorphism affect susceptibility to sepsis? This non-synonymous arginine-to-glutamine substitution occurs in the intracellular Toll/interleukin 1 receptor domain of the tivation , 30. TheSome limitations of our meta-analysis should be pointed out. First, the number of included studies and the sample sizes were moderate, and the heterogeneity was still existed in some subgroups in our meta-analysis, which may have contributed to the modest results. Some studies without sufficient information were excluded, and some subgroup analyses were not conducted in the small number of studies. Second, sepsis is a complex syndrome concerning different pathogens, different ethnicities, different age groups, and different underlying diseases. We could take only some of them into consideration because of their limited information. Third, the study population in our meta-analysis was focused on people of European ethnicity. Our conclusions may be not generalizable to Asian populations. Fourth, many genes are associated with sepsis. However, we could not address gene–gene interactions in this meta-analysis, owing to the lack of related information. Fifth, selection bias may exist because negative studies are difficult to publish. Sixth, the quality of our included studies was not assessed for their limited information. Seventh, we could discuss only the association between the TLR2 Arg753Gln polymorphism and sepsis risk in two genetic models for the lack of a mutant homozygote.In our meta-analysis, we pooled all available data related to potential links between the TLR2 Arg753Gln polymorphism and sepsis risk. The evidence suggested that the TLR2 Arg753Gln polymorphism could increase sepsis risk, especially in European populations, which may help us identify high-risk patients. Future large, well-designed epidemiological studies are required to validate this conclusion.Previous studies showed conflicting results regarding the effect of the TLR2 Arg753Gln polymorphism on sepsis risk.To the best of our knowledge, this is the first meta-analysis in which the relationship between TLR2 polymorphism and sepsis risk was explored.In our meta-analysis, we found that the TLR2 Arg753Gln polymorphism could increase sepsis risk, especially in European populations, based on previous studies.


Objective. This study aimed to investigate the association between three polymorphisms of renin-angiotensin system and the essential hypertension in the population of Burkina Faso. Methodology. This was a case-control study including 202 cases and 204 matched controls subjects. The polymorphisms were identified by a classical and a real-time PCR. Results. The AGT 235M/T and AT1R 1166A/C polymorphisms were not associated with the hypertension while the genotype frequencies of the ACE I/D polymorphism between patients and controls  were significantly different (p < 10−4). The genotype DD of ACE gene , the increasing age , obesity , dyslipidemia , and alcohol intake  were identified as the independent risk factors for hypertension by multinomial logistic regression. Conclusion. The DD genotype of the ACE gene is involved in susceptibility to hypertension. Further investigations are needed to better monitor and provide individualized care for hypertensive patients. The arterial hypertension is a great public health concern in both industrialized and developing countries. It affects 972 million persons over the world, around one-quarter of the adult population. Among the affected persons, 639 million are living in the developing countries . The artAmong the genetic markers commonly involved, the polymorphisms of several genes, including those encoding vasoactive metabolites such as the components of the renin-angiotensin system (RAS), have been proposed as candidates in association with essential hypertension. The special attention given to the RAS gene polymorphisms is not only due to the fact that its components play an important role in regulation of vascular homeostasis, but also because of the place of angiotensin I converting enzyme (ACE) inhibitors in the therapeutic management of the hypertension.The polymorphism in exon 2 of the angiotensinogen (AGT) gene, on chromosome 1q42, consists of a substitution of threonine by methionine at position 235 (235M/T). The insertion/deletion polymorphism of the gene encoding the angiotensin I converting enzyme (ACE) consists in the presence (I) or the absence (D) of a 287 bp Alu sequence in intron 16 of this gene on chromosome 17q2. The 1166A/C polymorphism was identified in the 3′ UTR (chromosome 3) of angiotensin II type 1 receptor (AT1R) gene and consists of a substitution of adenosine by cytosine in the messenger RNA. Previous studies focused on the relationship between these polymorphisms and cardiovascular diseases such as hypertension have reported conflicting data [The study focused on a population of Burkina Faso (West Africa). This study was approved by the Saint-Camille/CERBA ethical committee. All study participants gave their informed consent and were between 20 and 79 years old. A manual aneroid sphygmomanometer, with armbands adapted to patients and controls morphotypes, was used to measure blood pressure values (systolic and diastolic) by the auscultation method for each subject in a sitting or lying position after at least 10 minutes of rest.Hypertensive subjects (202) were recruited from the cardiology services in four medical centers of the city of Ouagadougou. The recommendations of scientific societies were used to define and classify the hypertension , 9. A toTwo measurements were made during the same visit, and the retained value was the mean value in the arm with the highest arterial pressure. A standardized questionnaire and clinical examination allowed the collection of data and excluded secondary hypertension and subjects under hormonal treatment to avoid the bias related to the hypertension definition.2. This allowed classifying the subjects into four different groups: subjects of low weight (BMI < 18.5 kg/m2), subjects of normal weight (BMI between 18.5 and 24.99 kg/m2), overweight subjects (BMI between 25 and 29.99 kg/m2), and obese subjects (BMI ≥ 30 kg/m2).Hypertension was defined as BP ≥ 140/90 mmHg. The body mass index (BMI) was determined for each subject by dividing the weight in kg by the square of the height in mThe venous peripheral blood was collected from each fasting subject for biochemical and molecular tests. Plasma levels of the following parameters including glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides were detected using an enzymatic method by the COBAS C311  automated analyzer.The genomic DNA was extracted from leucocytes using the “DNA Rapid Salting-Out” as described by Miller et al. .μL. Amplification was carried out in 30 cycles with a denaturation phase (94°C for 1 minute), annealing (58°C for 1 minute), and elongation (72°C for 2 minutes) for each cycle and a final extension of 10 minutes at 72°C. Given the fact that the D allele is preferably genotyped with respect to the I allele [The ACE I/D polymorphism (rs4646994) genotyping was performed according to the method described by Rigat et al. . A firstI allele , DD homoI allele , with spI allele . PCR proThe AGT 235M/T (rs699) and AT1R 1166A/C (rs5186) polymorphisms were detected by real-time PCR using TaqMan probes on the 7500 Fast Real-Time PCR Systems .χ2) allowed us to compare the differences in the distribution of genotypes and other study variables. Changes were considered statistically significant at p < 0.05. Odds ratio (OR) and confidence intervals (CI) at 95% were calculated to estimate the relative risk of hypertension for AGT 235M/T, ACE I/D, and AT1R 1166A/C polymorphisms associated with the continuous categorical variables  and discrete variables (sex (M/F), alcohol consumption (yes/no), tobacco consumption (yes/no), lack of physical activity (yes/no), and taking stimulants (yes/no)). The independent predictors of hypertension risk were determined by a multiple logistic regression analysis (forward stepwise method) using HTA status as dependent variable.SPSS version 20.0 was used for data analysis. The PowerMarker software Version 3.25 was used for the determination of the Hardy-Weinberg equilibrium and the calculation of allele and genotype frequencies. The Chi-square test (p < 0.05).p < 0.00001; D: OR = 2.68, 95% CI = 1.93 to 3.74, p < 0.00001). No homozygous genotype was obtained for the C allele (AT1R 1166A/C), which justifies the null frequencies reported in cases and in controls for this genotype.For each of the three polymorphisms studied , the genotypes distribution was in Hardy-Weinberg equilibrium for both patients and controls. Allelic and genotypic frequencies of these polymorphisms are presented in We then conducted a stratified analysis to assess the distribution of genotypes of each polymorphism in the different study groups. These results are shown in Multiple logistic regression analysis (forward stepwise method), using the hypertension status as the dependent variable, including the conventional cardiovascular disease risk factors  and new risk factor, such as DD genotype, showed that obesity, increasing age, dyslipidemia, DD genotype, and alcohol intake are independent risk factors for HTA, in decreasing order .The main purpose of this study was to investigate the existence of a possible association between RAS genes polymorphisms and the hypertension and also to identify the main risk factors for this chronic condition in the Burkinabe population. Strong female predominance (58.56%) was found in our study. Yaméogo et al. and Baragou et al. also found similar frequencies in their studies, 56.8% of the hypertensive patients in Burkina Faso  and 55.1The age of study population varied from 20 to 79 years. This is because there was an important proportion of young subjects (under 50 years) among hypertensives, and so we needed to have young subjects in controls group to match cases. However, the young age of some controls may constitute a limitation of this study. Indeed, among the young controls, some may be hypertensive in the future skewing the selection of controls subjects.The different approaches used in studies focused on genetic susceptibility to disease in African populations have been previously described by Sirugo et al. . Among tJeunemaitre et al. reported an association between the TT genotype of the AGT gene and the risk of hypertension in Utah and France . Subsequp < 0.0001). Mehri et al. [The DD genotype of the ACE gene was present in 35.78% of controls, compared to 66.83% of hypertensive patients. This result showed a strong association between the ACE I/D polymorphism and the risk of hypertension in the Burkinabe population . This obesity frequency was twice as high in women as in men . The high prevalence of obesity in developing countries is related to the socioeconomic level of the population [Our results showed a strong association between the ACE I/D polymorphism and the development of hypertension. Thus, DD genotype is a predictor of hypertension risk, independent of other environmental factors. This work has also shown that obesity prevalence was 11% among controls and was the major risk factor of hypertension among the Burkinabe population (OR = 4.84, 95% CI = 2.96 to 7.92; pulation , along wpulation .For the three polymorphisms studied, we find evidence of the association with hypertension risk only for the ACE I/D polymorphism. However, Niu et al.  and MehrThe reported discrepancies reflect genetic, cultural, and ethnic diversity within populations of study, people who mostly live in different environmental contexts, and are therefore exposed to various problems. Thus, the negative associations reported may be due to these differences and possible sampling bias . In addiAGT 235M/T and AT1R 1166A/C polymorphisms showed no association with the risk of developing hypertension. However, the ACE gene DD genotype predisposes to the occurrence of hypertension in the Burkinabe population. Other major risk factors identified are obesity, advancing age, dyslipidemia, and alcohol consumption. ACE I/D polymorphism can serve as a marker for early diagnosis of hypertension if we have similar findings elsewhere. More studies involving ACE I/D polymorphism with hypertension therapeutic responses are still needed to better monitor and provide individualized care for hypertensive patients.


ACE) Insertion/Deletion (I/D) polymorphism and Familial Hypercholesterolemia (FH) has been not fully investigated in all the ethnicities. In this study we sought to determine the frequency of I/D polymorphism genotypes of ACE gene in Saudi patients with FH.The study of the association between genotype and phenotype is of great importance for the prediction of multiple diseases and pathophysiological conditions. The relationship between angiotensin converting enzyme .This is a case–control study carried out purely in Saudi population. Genomic DNA was isolated from 128 subjects who have participated in this study. ACE gene I/D polymorphism examined in this study has no role in predicting the occurrence and diagnosis of FH.Our data suggest that  Familial hypercholesterolemia FH, OMIM 143890) is an inherited disorder of lipoprotein metabolism, transmitted in an autosomal dominant manner and clinically characterized by elevated serum levels of total and low-density lipoprotein (LDL) cholesterol, the presence of tendon xanthomas and premature atherosclerosis43890 is . PopulatGene polymorphisms are markers of biologic diversity, and some genotypic variations correlate with specific phenotypes relevant to the human diseases. However, it is not clear whether many of these variants are involved in the pathogenesis of diseases or are merely in proximity to other pathogenic genetic factors-a phenomenon known as linkage disequilibrium. Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is responsible for inter individual differences in ACE plasma levels. It is known that the frequency of ACE D alleles varies in different ethnic groups. A previACE is a zinc metalloprotease that is widely distributed on the surface of epithelial and endothelial cells. Its gene consists of 26 exons and spans 21 kb on the human chromosome 17. The sequence codes a 1306-amino-acid protein, including a signal peptide. It has a common polymorphism that consists of the presence  or the absence  of a 287-bp Alu repeat sequence within intron 16. Although the I/D polymorphism is in the intronic region of the ACE gene, studies have shown that the DD genotype is strongly associated with increased plasma or serum ACE levels. ACE actn = 64) were recruited from Medical and laboratory staff at KKUH, and individuals attend KKUH for routine checkup and who were not having chronic metabolic/ medical disease. The research protocol was approved by the Institutional Review Board at KKUH (E-12-829). All participants provided written informed consent prior to enrollment into the study.In this study 64 subjects diagnosed with FH, based on the Deutch working group classification criteria. PatientParticipants were advised to fast overnight for at least 10 hours prior to sample collection. Five mL of blood sample was collected from every participant; 3 mL of the serum sample was used for biochemical parameters like Total Cholesterol (TC), Triglycerides (TG), HDL-C and LDLC to confirm the FH and 2 mL of EDTA blood sample was used for molecular investigation.Serum samples of TC and TG were measured by the standard enzymatic method  using an automated RA-1000 . Serum LDL-C and HDL-C levels were measured using commercially available enzyme assay kits .2, 10x PCR buffer, dNTPs, 10 units of Taq DNA polymerase  and the 60 ng template DNA. The PCR was performed in a thermal cycler . The cycling and amplification conditions were as follows; an initial denaturation was set up for 5 minutes at 95°C followed by 35 cycles of denaturation for 30 seconds at 95°C, annealing for 30 seconds at 59°C, extension for 45 seconds at 72°C and the final extension was at 72°C for 5 minutes. The insertion band is considered as 490 bp which represents the I allele and 190 bp is identified as deletion band (without 287-bp Alu insertion) which represents the D allele and the I/D band was 490/190 bp which is considered as the heterozygous , dominant (DD + DI vs. II) and recessive (DD vs. ID + II) genetic model. Z-test was used to determine the significance of the pooled ORs, and p value < 0.05 was considered significant. The effect of I/D genotypes of ACE gene was analyzed using general linear model ANOVA for clinical characteristics. A level of p <0.05 was considered statistically significant.All the statistical analyses were carried out using SPSS  software version 19.0 for Microsoft Windows®. Clinical characteristics of all subjects were expressed as mean ± SD. Continuous variables were compared between the groups using two-tailed student’s p < 0.05). The LDL-C level was 4.8 ± 0.55 mmol/L in FH individuals compared to 3.1 ± 0.32 mmol/L in the control group (p > 0.05). There was significant difference in the Age, TG, TC and LDL-C levels between the FH subjects and the healthy controls (p < 0.05), but there was no difference between FH subjects and healthy controls in HDL-C and gender (p > 0.05).The demographic and the biological data of all the patients participating in this study are shown in Table p = 0.21 (95% CI = 0.7385-3.893) and OR = 1.481, p = 0.12 (95% CI = 0.8953-2.449) (Table p = 0.43 (95% CI = 0.3403-1.597)  genotypes and more ID (32.9%) genotypes than controls. However, there was no significant difference in the allelic frequency between the patients and controls.Previous studies addressing the association between FH and ACE gene polymorphism focused on the potential risk of CHD coronary heart disease associated with ACE gene polymorphism in FH patients. For example, O’Malley et al. showed tA few studies have been conducted in Saudi Arabia and Middle East looking at the association between ACE gene polymorphism and certain diseases. We have reported previously an association between ACE gene polymorphism and G6PD deficiency. El-HazmIn contrary to that, Dzimiri et al. showed nIn conclusion, our study has not shown an association between I/D polymorphism of ACE gene and FH in the Saudi populations. However, considering the relatively small sample sizes of our study, a firm conclusion cannot be made and larger studies in more well-characterized subjects should be conducted in the future.The authors declare that they have no competing interests.AKK participated in the design of the study and main investigator of this study. KTS has confirmed the FH patients and drafted the manuscript. AW has carried out the DNA isolation. AMS was the Co-I of this study. SM was an endocrinologist, helped in the FH cases, reviewed and edited the manuscript. HRMW carried out the lipid profile analysis. AMY has collected the control samples. TW has helped in this project with statistics. IAK: Design the study, performed the genotyping, written and edited the manuscript. All authors read and approved the final manuscript.


Single nucleotide polymorphisms (SNPs) in the interleukin-17 (IL-17) gene have been shown to be correlated with susceptibility to cancer. However, various studies report different results of this association. The aim of the present work was to clarify the effects of IL-17A G197A (rs2275913) and IL-17F T7488C (rs763780) polymorphisms on cancer risk. We performed systematic searches of the PubMed and CNKI databases to obtain relevant publications. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the association of rs2275913 and rs763780 polymorphisms with cancer risk. Data were extracted from the selected studies, and statistical analysis was conducted using the STATA software. Our results indicated that rs2275913 and rs763780 polymorphisms significantly increase cancer risk, especially in gastric cancers. Subgroup analysis suggested the existence of a significant correlation between rs763780 polymorphism and cancer susceptibility in Caucasian populations. This updated meta-analysis confirms that rs2275913 and rs763780 polymorphisms are highly associated with increased risk for multiple forms of cancer. According to the latest global statistics on cancer, approximately 14.1 million new cancer cases and 8.2 million cancer-related deaths occurred worldwide in 2012Inherited factors leading to the development of cancer are not clearly understood, but the roles of cytokines in tumour immunity and carcinogenesis have been well established78111213Meta-analysis is a statistical technique that combines results from different individual studies to produce a comprehensive assessment of the major findings with enhanced accuracy11121314161718192021222324252627282930Through primary literature retrieval from Pubmed and CNKI databases, we identified 95 studies that investigated the effect of IL-17 polymorphisms on cancer risk. After screening the titles and abstracts according to the preferred reporting items for systematic reviews and meta-analyses PRISMA, , 55 studIL-17A G197A polymorphism (rs2275913).Overall, our meta-analysis found a borderline association between rs2275913 polymorphism and increased cancer risk in all genetic models .A significant association was found between rs763780 and cancer susceptibility in 3 different comparison models , but not Caucasians. When subgroup analysis was performed based on cancer types, a significant association was found between rs2275913 polymorphism and risk of gastric/cervical cancer. Interestingly, individuals with the rs2275913 AA genotype showed decreased risk of colorectal cancer as compared to individuals with the GG or GA genotypes. However, only two eligible studies examined IL-17 polymorphisms in colorectal cancer, and therefore, the results may need to be further confirmed. Interestingly, a significant association was found between the rs763780 variant and cancer risk in both the Asian and Caucasian populations. This meta-analysis is, to our knowledge, the first study showing that rs763780 polymorphism increases cancer risk in the Caucasian population.et al.et al.et al.451416242731A meta-analysis by Niu We conducted sensitivity analysis to confirm the validity of the results presented in our meta-analysis, and studies in which the genotype frequencies in the control group deviated from the HWE were excluded. Results showed that no individual study skewed the overall OR value.Some limitations of the present meta-analysis should be addressed. First, although significant associations were found between the two polymorphisms and the risk of cancer in multiple genetic models, some potential sources of heterogeneity, such as source of controls, lifestyle, and environmental exposures, were not explored. In addition, some cancer types included in this meta-analysis were investigated only in 1 or 2 studies , which lOur study represents a comprehensive meta-analysis of the role of IL-17A rs2275913 and IL-17F rs763780 polymorphisms in cancer risk. The results demonstrated that these two polymorphisms significantly increase the risk of development of cancer, particularly gastric cancer. Further large-scale, multicentre studies are required to confirm the pre-diagnostic effect of IL-17 gene polymorphisms on the risk of cancer.Systematic article search and quantitative analysis were performed, and written reports were generated according to the Meta-analysis of Observational Studies in Epidemiology guidelinesStudies included in our meta-analysis were required to meet the following criteria: (1) a case-control design; (2) the study goal was to evaluate the association of IL17A rs2275913 and IL-17F rs763780 polymorphisms with cancer risk; (3) the study offered available information on genotype frequency, (4) the controls used had no malignant disease. The following were used as our exclusion criteria: (1) the study was a repeat studies, reviews, or abstracts; (2) the study design was based on family cancers; (3) the study did not include a control group; (4) the study did not investigate the effect of polymorphism; (5) duplicate data.Two authors independently selected the potentially relevant studies for data extraction. We screened the titles and abstracts of the studies that met our inclusion criteria. If the content of the abstract was relevant, full articles were read to extract related information. For each eligible study included in our meta-analysis, we obtained information pertaining to first author, years of publication, country of origin, racial ancestry, cancer types, source of control, genotyping method, total number of cases and controls, and P value of Hardy–Weinberg equilibrium (HWE). All cancers were confirmed by histology or pathology. All the case and control groups were well controlled.We applied re-sampling statistic to examine the robustness of the associations, and 10000 re-sampling analyses were conducted using the bootstrap re-sampling procedureThe strength of association between IL-17A rs2275913 and IL-17F rs763780 polymorphisms and cancer risk was assessed as ORs with corresponding 95% CIs based on the allele frequencies in cases and controls of each study selected. The summary OR was calculated according to Woolf’s method. Five different ORs were calculated: dominant model (BB+AB vs. AA), recessive model (BB vs. AA+AB), homozygote comparison (BB vs. AA), heterozygote comparison (AB vs. AA) and allele comparison (B vs. A), the A represents the major allele, and the B represents the minor allele. The Chi-square-based Q statistic was implemented to assess heterogeneity among the studies2 test statistical and significance was considered at P < 0.10. In case of a significant heterogeneity, the pooled ORs were analyzed using a random-effects model, otherwise a fixed-effects model should be used. To evaluate the ethnicity-specific and control-specific effects, subgroup analyses were conducted by source of controls, cancer types, controls whether satisfied HWE or not, and features of the population such as ethnicity. Additionally, to estimate the possible sources of bias, we considered the Egger’s test and Begg’s funnel plot. All statistical analyses were calculated with the software STATA . P-values less than 0.05 were considered statistically significant.The effect of heterogeneity using IHow to cite this article: Dai, Z.-M. et al. Role of IL-17A rs2275913 and IL-17F rs763780 polymorphisms in risk of cancer development: an updated meta-analysis. Sci. Rep.6, 20439; doi: 10.1038/srep20439 (2016).


The prevalence of childhood leukemia is increasing rapidly all over the world. However, studies on maternal benzene exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have not been systematically assessed. Therefore, we performed a meta-analysis to investigate the association between maternal solvent, paint, petroleum exposure, and smoking during pregnancy and risk of childhood ALL.st, 2013 were identified by searching the PubMed, EMBASE, Cochrane library and the Web of Science databases. The effects were pooled using either fixed or random effect models based on the heterogeneity of the studies.Relevant studies up to September 1Twenty-eight case-control studies and one cohort study were included for analysis, with a total of 16,695 cases and 1,472,786 controls involved. Pooled odds ratio (OR) with 95% confidence interval (CI) for ALL was 1.25  for solvent, 1.23  for paint, 1.42  for petroleum exposure, and 0.99  for maternal smoking during pregnancy. No publication bias was found in this meta-analysis and consistent results were observed for subgroup and sensitivity analyses.Childhood ALL was associated with maternal solvent, paint, and petroleum exposure during pregnancy. No association was found between ALL and maternal smoking during pregnancy. Avoidance of maternal occupational and environmental benzene exposure during pregnancy could contribute to a decrease in the risk of childhood ALL. In recent years, leukemia has become the most common cancer of children under the age of 15 In previous studies, benzene has been identified as a carcinogen for leukemia among exposed workers Among environmental risk factors, the impact of solvent, paint, petroleum products and cigarette smoking on the development of childhood ALL have been extensively investigated. Studies have shown that cigarette smoking is leading contributor of benzene in non-occupational environments st 2013. The search terms were: (childhood OR child OR infant) AND  AND . Search strategies are shown in A comprehensive review of the literature was conducted by searching PubMed, Embase, the Cochrane library and Web of Science databases up to September 1Studies were selected for inclusion based on the following criteria: 1) the information to estimate the relationship between benzene exposure and risk for childhood leukemia (effect size) in terms of odds ratio (OR), relative risk (RR) and hazard risk (HR) was available; 2) the study examined maternal exposure during pregnancy; 3) the study design was a cohort or case-control study; 4) current smoking during pregnancy was included; and 5) studies with children who had Down’s syndrome or any neoplastic disease were excluded. When multiple publications on the same study population were identified or study populations overlapped, the most recent and complete study was included in the meta-analysis. Furthermore, if a variable representing “any” solvent or paint or petroleum exposure was reported, these data were used. Only studies published in English were included. For reliability,two co-authors (Zhou and Zhang) reviewed all the identified citations independently, and articles met the criteria of inclusion were finally included in the present meta-analysis. Disagreements were resolved by reaching consensus between the two co-authors.Information from studies was also extracted independently by two researchers, with disagreements resolved by consensus. The following terms of data were collected: first author’s last name, country studied, study design, study period, age range, matching factors, adjusting factors, exposure definition, the number of cases and controls, effect estimate  with 95% CIs, and assessment of exposure. Most of the time, the effect estimate were extracted from the papers directly, however, the ORs were calculated when the paper only reported frequencies. All literatures analyzed in this meta-analysis are publicly published and are accessible in the database using the citation. The data for each literature are extracted using designed standard data extract form, which are available to all readers as required.The Newcastle-Ottawa-Scale (NOS) was used to assess the quality of papers 2I) with corresponding P-values and the level of significance was set at P = 0.10P<0.10 or 2I≥50%, the heterogeneity was considered statistically significant, and the DerSimonian and Laird random-effect model was used; Otherwise, the Mantel-Haenszel fixed-effect model was used to calculate the pooled ORs Meta-analysis was performed using Stata version 12.0 . ORs, RRs, and HRs with 95% corresponding CIs were used (HR and RR were directly considered as OR) to assess the association between benzene exposure and risk for childhood ALL. Heterogeneity among studies was estimated by chi-squared test and Cochran Q score  and thirteen were in moderate quality (nine studies scored 6 and four studies scored 5).2I = 33.0%, P = 0.176; 2I = 14.1%, P = 0.322, respectively), however significant heterogeneity was observed in paint . The results in the meta-analysis showed an increased risk of ALL in those who were exposed to solvent or petroleum or paint .As shown in 2I = 41.9%, P = 0.032) among these studies.Results for maternal smoking during pregnancy are shown in The results for subgroup analysis of childhood ALL incidence and maternal smoking during pregnancy are presented in P = 0.996; Begg’s test: P = 0.764), paint , petroleum , and smoking .Using Egger’s and Begg’s test, no publication bias was observed in this meta-analysis seen in , for solOur meta-analysis included data from 29 studies with 16,695 cases and 1,472,786 controls. Based on the present meta-analysis, the overall data demonstrated that the ALL was significantly associated with maternal solvent, paint, or petroleum exposure. For maternal smoking during pregnancy, the same conclusion has been concluded for risk of childhood ALL in previous meta-analysis  Exposures to solvent and paint have been suggested as potential risk factors of childhood leukemia Petroleum is another main source of environmental benzene exposure. Studies have shown that childhood leukemia is associated with various exposures to petroleum. A study by Swaen et al. indicated leukemia mortality was associated with gasoline consumption, number of household cars, distance to a gasoline station, and distance to main road as evaluation indexes of petroleum Several studies specifically evaluated childhood ALL risk associated with maternal smoking during pregnancy. However, only three case–control studies To detect the source of heterogeneity, we conducted subgroup analysis by region, year, child’s age, sample size of each study, high or moderate study quality and whether the effect size had adjusted by maternal education, maternal age, household income or ethnicity groups. Both fixed and random effect model were used for each subgroup. No heterogeneity was found across these subgroup variables, and the result of each subgroup was similar to the overall effect size. However, we did find the heterogeneity for types of study design and low quality study in our preliminary analysis. Therefore, we analyzed case-control studies and cohort studies separately and excluded the one low quality study and no heterogeneity was observed in this meta-analysis.Our study may have the following limitations. First, interviewer bias: 1) The data in most studies we analyzed were collected by personal interview Despite the limitations, there are several strengths of this study. First, twenty-nine studies cover a broad region and long study period. Second, all the eligible studies had high or moderate research design quality. Third, no publication bias was observed based on Egger’s test and Begg’s test. Finally, our eligible literatures had comprehensive matching factors and adjusting factors, thus reducing the corresponding errors.Based on the present meta-analysis, we concluded that maternal solvent, paint, petroleum exposure during pregnancy are associated with ALL. Avoidance of maternal benzene exposure during pregnancy might contribute to a decrease in the risk of childhood ALL.This meta-analysis suggested the directions for future study are: 1) conduct large sample cohort studies or high quality case–control studies; 2) investigate new risk factors for childhood leukemia, such as drug use, traffic exhaust, alcohol consumption, infection, etc.; 3) explore the exposure during pregnancy, as well as before pregnancy and childhood exposure; 4) explore dose-response relationships; 5) assess gene-environment interaction, as the mechanism of childhood leukemia is likely to associate with gene–environment interactions Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


MTHFR C677T and A1298C polymorphisms and the risk ofNSCL/P. In light of this gap, a meta-analysis of all eligible case-control studies wasconducted in the present study.The methylenetetrahydrofolate reductase (MTHFR) is thought to beinvolved in the development of nonsyndromic cleft lip with or without cleft palate(NSCL/P). However, conflicting results have been obtained when evaluating the association between maternal 2) indicated no obvious heterogeneity among studies.A total of 15 case-control studies were ultimately identifiedafter a comprehensive literature search and Hardy-Weinberg equilibrium (HWE) examination. Cochrane’s Q test and index of heterogeneity . The results showed that the TT genotype in mothers increased the likelihood of havingNSCL/P offspring 1.25 times (95% CI: 1.047-1.494) more than the CC homozygotes. Meanwhile, maternal TT genotype increased the risk of producing NSCL/P offspring in recessivemodel . However, the CT heterozygote and the CT+TTdominant models had no association with NSCL/P offspring compared with the CC wild-typehomozygote model. Subgroup analyses based on ethnicity indicated that maternal TT genotype increased the likelihood of having NSCL/P offspring in Whites  and Asians  in recessive model. Also, subgroup analyses based on source of control showed that mothers with the 677TT genotype hada significantly increased susceptibility of having NSCL/P children in hospital based population (HB) when compared with CC homozygotes  and un-der the recessive model . Furthermore, maternal A1298Cpolymorphism had no significant association with producing NSCL/P offspring .MTHFR C677T polymorphism is associated with the risk of generating NSCL/Poffspring, and being a 677TT homozygote is a risk factor. MTHFR A1298C polymorphismwas not associated with generating NSCL/P offspring. However, further work should be performed to confirm these findings. Cleft lip and palate is one of the most common congenitaldefects in humans , which iMTHFR) enzymeis particularly attractive, because this enzyme isresponsible for folate-dependent metabolism ofhomocysteine, which catalyses the reduction of5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate,the predominant circulatory form offolate and the carbon donor for the remethylationof homocysteine to methionine  and A1298C(rs1801131) for which their roles in the mechanismsof folate enzyme have been extensivelyinvestigated . The 6773 and A12in vivo , 16. Thein vivo , 17.MTHFR which encodes a keyprotein in folate and methionine metabolism  risk factors for having a child with NSCL/P?Are maternal MTHFRpolymorphisms and NSCL/P children. 2. Casecontrolstudy design; considering the heterogeneityin different study designs, we only focused on casecontrolstudies. Cross-sectional studies, case-parenttriads, and transmission disequilibrium tests (TDT)designed studies were not included. 3. Cases weremothers who have children with NSCL/P. Controlgroup were mothers without NSCL/P children andselected from the general population or hospitalbased population. 4. Provided distributions of thematernal MTHFR C677T and/or A1298C genotypes. 5. Control groups in studies did not deviate fromHardy-Weinberg equilibrium (HWE).1. Explored the association of maternal We did not consider the genotyping method. Weonly included information available from the publicationsand did not seek additional informationby contacting primary authors. Studies were excludedif the disease was defined as either familialNSCL/P or orofacial clefts. Case reports, lettersand review articles were excluded from the study.th March 2013. MeSH terms included"cleft lip" and "methylenetetrahydrofolatereductase (nadph2)". Free words included "cleftlip", "cleft", "lip", "methylenetetrahydrofolate"and "MTHFR". We extended our search to reviewthe reference lists of retrieved articles and performedmanual searching as a supplement. Whena study had duplicate publication, only the mostinclusive publication was considered. The fulltexts of candidate articles were examined by twoinvestigators independently.A comprehensive literature search was performedusing PubMed, Springer, Elsevier DigitalDissertations Databases, Scopus, and ISI web ofknowledge with MeSH terms retrieval and freewords retrieval for relevant articles published inEnglish up to 15MTHFR C677T or A1298Cgenotypes among cases and controls. For studies withmultiple gene polymorphisms, only data concerningMTHFR polymorphisms were included in the analysis.No modification of original data was performed.In addition, HWE was calculated based on the genotypesamong controls. The data were extracted frompublished manuscripts, thus no research ethics boardapproval was necessary.Data from each eligible study were extracted oncustom-made data collection forms by two authorsindependently. For inconsistent evaluations, agreementswere reached following discussion in our studygroup. For each study, the following characteristicswere collected: first author, publication year, country,source of controls, characteristics of study population, and distributionsof the maternal MTHFR C677T and A1298Cpolymorphisms from expectation under HWE incontrols. The strength of the association betweenthe polymorphisms and NSCL/P was measured byORs with 95% confidence intervals (CIs). The statisticalsignificance of the observed OR was testedby Z-test. For the C677T polymorphism, we firstlyused wild-type CC genotype as the reference groupto evaluate the effects of the CT and TT genotypeson NSCL/P susceptibility. Then we estimated theeffects of CT/TT versus CC and TT versus CT/CCassuming the dominant and recessive models ofthe T allele. Same procedures were also performedon the A1298C polymorphism. Furthermore, subgroupanalyses were performed based on source ofcontrols and ethnicity. Heterogeneity assumptionbetween studies was examined by the Chi-squarebased on Q-test and I-square value  was used to perform all statistical analyses.Goodness-of-fit chi-squared test was used to assessthe frequencies of re value . A ﬁxedeSensitivity analyses using the step by step exclusionmethod were conducted to assess whethereach individual study affected the final results.Publication bias was evaluated by Begg’s test,the Egger’s asymmetry test and visual inspectionof funnel plots. All the P values were for a twosidedtest and p<0.05 was considered statisticallysigniﬁcant.Sensitivity analyses using the step by step exclusionmethod were conducted to assess whethereach individual study affected the final results.Publication bias was evaluated by Begg’s test,the Egger’s asymmetry test and visual inspectionof funnel plots. All the P values were for a twosidedtest and p<0.05 was considered statisticallysigniﬁcant.Fifteen case-control studies were identified viaour search strategy, for which 8 were concernedwith C677T exclusively, while 7 studies had analyzedboth variants .The characteristic information of the includedstudies such as first author, publication year,country, ethnicity, source of controls, samplesize (case/control), genotype distributions (case/control) are presented in MTHFR C677T polymorphism,there were significant heterogeneityfor heterozygote comparison (CT versusCC: Ph=0.008) and dominant model comparison(CT+TT versus CC: Ph=0.004), but not forthe homozygote comparison (TT versus CC:Ph=0.076) and the recessive model comparison(TT versus CT+CC: Ph=0.102)  ,Fig 2.  h>0.05, , Fig 3.Regarding maternal C677T polymorphism andNSCL/P offspring, 15 studies with a total of 2442cases and 4655 controls were included. MaternalTT genotype contributed to elevated risks ofhaving an NSCL/P child compared with the CCwild-type genotype , and this effect appeared only in the HBpopulation after subgroup analysis by source of controlsand ethnicity. Under the recessive model, 677TTconferred increased susceptibility to havinga child with NSCL/P when using CT+CC asreference ,and this effect appeared in Asians , Whites , and the HB population  after furthersubgroup analysis. However, the CT heterozygoteand the CT+TT dominant model had no associationwith bearing NSCL/P offspring whencompared with CC wild-type genotype  , Fig 2.MTHFR A1298C polymorphism and NSCL/Poffspring, 7 studies with 1032 cases and 2095controls were included. There was no associationbetween the maternal MTHFR A1298C polymorphismand having NSCL/P offspring under all geneticmodels, since the null value of all ORs  was well inside the 95% confidence intervals. Funnel plots of all studies revealed noasymmetrical distribution of ORs Figes-5,suggeMTHFR polymorphisms(C677T and A1298C) and risk of havingNSCL/P offspring. Results showed that motherscarrying the 677TT genotype had an increasedsusceptibility to have an NSCL/P offspring underboth the recessive model and the CC homozygotemodel, but the CT heterozygote andthe CT+TT dominant models had no associationwith bearing NSCL/P offspring when comparedwith CC genotype. This suggests that only thematernal 677TT genotype is a risk factor forhaving NSCL/P offspring. Subgroup analysesbased on ethnicity and source of control showedthat under the recessive model, maternal 677TTgenotype increased the risk of having NSCL/Poffspring in Whites, Asians, and the HB population,providing further evidence that the TTgenotype is the risk factor. However, maternalMTHFR A1298C polymorphism had no associationwith having NSCL/P offspring under allgenetic models, and results did not differ whensubgroup analyses were undertaken.In the present meta-analysis, we focused onthe relationship of maternal MTHFR C677T and A1298C polymorphismswere not independently associated withCLP with pooled ORs of 1.2 (95% CI: 0.9-1.5)and 1.0 (95% CI: 0.7-1.2). Results from the codominantmodel were similar to the study byLuo et al.  ismore related and more important with regardsto NSCL/P.Furthermore, Verkleij-Hagoort et al.  andLuo net al.  which coMTHFR polymorphismshave been widely examined but provided inconsistentresults. This absence of consensusamong individual studies might be due to differentethnicities and study populations, differentlaboratory procedures used for genotyping,variable environment and diet, selection biasfrom both cases and controls subjects, and insufficientsample size  in neural tubedefect cases  exists between ct cases , 53, howMTHFR C677T polymorphism and riskof having an NSCL/P offspring, and confirmmothers with the 677TT genotype are susceptibleto have a child with NSCL/P. Nevertheless,in view of the limitations of the present study,our findings should be interpreted prudently.Further work, especially those that address thecombined effects of genetic and environmentalfactors on a specific phenotype of orofacialclefts should be performed to evaluate thesefindings.The results of this study give supporting evidencefor significant association between maternal


P = 0.009; I2 = 52%) and cohort study . In addition, high selenium level was associated with GC mortality risk . In summary, this meta-analysis suggested that selenium might inversely associated with GC risk and GC mortality.To clarify the effects of selenium level on the risk of gastric cancer (GC) and GC mortality, a meta-analysis was performed. Related studies were identified from PubMed, EMBASE, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM). Pooled ORs and 95% CIs were used to assess the strengthof the associations. A total of 8 studies including 17834 subjects were involved in this meta-analysis. High selenium level was associated with GC risk in case-control study (OR = 0.62, 95% CI 0.44–0.89,  Gastric cancer (GC) represents a serious health problem on a global scale . It is hP = 0.044)  or “gastric cancer” or “stomach tumor” or “stomach carcinoma” or “carcinoma of stomach”) and (“selenium” or “Se”). The references from retrieved articles were alsosearched. There was no limit set in the searches.Studies included in this meta-analysis have to meet the following criteria: (1) case–control study or cohort study studying on association between selenium and risk of GC or GC mortality; (2) all patients with the diagnosis of GC confirmed by pathological or histological examination; (3) sufficient published data about sample size, odds ratio (OR), and their 95% confidence interval (CI). Studies wereexcluded when they were: (1) not case–control study orcohort study; (2) duplicate of previous publication; (3) based on incomplete data; (4) meta-analyses, letters, reviews, or editorial articles.Data were independently extracted by two reviewers using a standardized data extraction form. Discrepancies were resolved by discussion and if consensus was not achieved the decision was made by all the reviewers. The title and abstract of all potentially relevant articles were screened to determine their relevance. Full articles were also scrutinized if the title and abstract were ambiguous. The following information was collected from each study: authors, year of publication, study design, race, age, sex, years of follow-up, sample size, sample collection, GC location, and covariant.P-values < 0.1. Dependent on the results of heterogeneity test among individual studies, the fixed effect model (Mantel–Haenszel) or random effect model (DerSimonian and Laird) was selected to summarize the combined OR and their 95% CI. The significance of the pooled OR was determined by the Z test. Subgroup analyses were carried out bystudy design, race, gender, smoking status, years of follow-up, sample collection, and cancer location, if possible. Publication bias was investigated with Egger's linear regression test. All the P values were two sided. P value less than 0.05 was considered statistically significant.Statistical analysis was conducted by using STATA statistical package . The association of selenium leveland GC risk or GC mortality was estimated by OR with 95% CI. The heterogeneity was tested by the Q-statistics with


FABP2) is an intracellular protein expressed exclusively in the enterocytes of proximal small intestine. FABP2 has a high affinity for saturated and unsaturated long-chain fatty acids and is believed to be involved in the absorption and transport of dietary fatty acids.Fatty acid-binding protein 2  assays using purified DNA.p < 0.05). Statistical analyses failed to show any type of significant association of the polymorphism between cases and controls. However logistic regression analyses was suggests that the TT genotype is significantly associated with male patients (p = 0.001). None of the allele or genotypes of FABP2 A54T was associated with T2DM cases versus the controls , p = 0.25; TT genotype, OR = 0.66 (0.39-1.11), p = 0.11; T allele, 0.82 (0.67-1.02), p = 0.08).Clinical data and anthropometric measurements except age, glucose levels and lipid profile of the patients were significantly different from those of the controls (FABP2 gene is not potential contributor to the risk of T2DM and related traits in a Saudi population. However TT genotype is a risk factor for the disease in males.In conclusion, this study suggests that the above named variant in  Type 2 diabetes mellitus (T2DM) is a chronic degenerative disease, phenotypically and genetically characterized by insulin resistance (IR) in insulin-target tissues, and impaired insulin secretion from pancreatic β-cells . T2DM afFABP2) has been studied as one of the marker, due to its role in the uptake, intracellular metabolism and excretion of long chain fatty acids. This gene is located on 4q28-q31 chromosomal region, consist of approximately 3.4 kbs. Many polymorphisms in FABP2 gene have already linked with metabolic phenotypes. The most extensively studies polymorphism was Alanine54threnonine (A54T) substitution at codon 54 of exon 2 that results from G to A nucleotide substitution and affects primary protein structure [Genome Wide Association Studies (GWAS) are powerful tools to identify genetic variants that are associated with common diseases. So far, GWAS identified at least 50–52 genetic loci robustly associated with T2DM . Severaltructure ,10. Thistructure .FABP2 variants to risk of T2DM in a Saudi population, since this polymorphism results in a functionally altered FABP2 protein which confers susceptibility to metabolic disorders like T2DM, thereby to contribute to the personalized prevention of this condition and A54T polymorphism has been associated with T2DM disease in many but not all studies.The aim of the present study was to investigate the contribution of A54T genetic polymorphism identified by Baier et al  in the FThis is a case–control study carried out in King Saud University, Riyadh, Saudi Arabia. In this study we have collected in about 900 subjects; 438 T2DM cases and 460 healthy controls from the capital city. All the normal controls were selected from the general population based on normal glucose values and non-obese subjects. The details of the collection of patients, inclusion and exclusion criteria were described in the prior publication . Ethical5 mL of the venous blood was collected into plain (coagulated) and EDTA (anticoaggulated) tubes. Plain vacutainer consist of 3 mL of the serum sample was used to analyze the biochemical parameters and 2 mL of the EDTA sample was used for molecular analysis. Genomic DNA was extracted from peripheral blood leukocytes using Norgen DNA extraction kit . DNA samples were stored at -80°C. The rs1799883 polymorphism was genotyped using a TaqMan® SNP genotyping assay (Assay ID: C_2834835_10) on a 7300HT sequence detection system . Primers and probes were obtained from Applied Biosystems as Assays-by-Design™. Cases and controls were ensured to have even treatment during the assay procedure, and each plate included negative controls (with no DNA). Plates were read on the ABI Prism 7300 using the Sequence Detection Software (Applied Biosystems) using 40 PCR cycles . Measurements were repeated for samples with failed genotypes. Assays that did not show >95% concordance were discarded and replaced with alternative assays with the same tagging properties.FABP2 gene in patients were compared to controls by chi-square analysis. The distribution of the genotypes deviates from Hardy-Weinberg equilibrium (HWE). Clinical characteristics of all the subjects were expressed as mean ± SD. Continuous variables were compared between the groups using two-tailed student t-test. Odds ratios (ORs) and 95% CI, with adjustment for age, sex and BMI were calculated using multiple logistic regression analysis. All tests were conducted at the p < 0.05 level of significance.All statistical analysis was carried out using the statistical program i.e. statistical package for social sciences . The difference of mean age of patients and controls were significantly different (Table p > 0.05). T2DM subjects appear to have higher levels of SBP, DBP, fasting glucose, insulin, HOMA-IR and lipid profile and waist (p < 0.05).In this case–control study, we have carried out in almost 900 subjects; 438 patients with T2DM  and 460 normal control subjects . The mean age was 60 years for patients and 59 years for the control group. Clinical and anthropometric data are revealed in Table FABP2 A54T polymorphism and the frequency of A and T alleles in patients and controls have been tabulated in Table χ2= 0.37, p = 0.54). Genotyping of the A54T polymorphism in the FABP2 gene revealed that the allelic frequency of T allele was 0.285 in cases and 0.248 in controls (OR-0.82 (95% CI = 0.67-1.02); p = 0.08). There were no significant differences in both the genotypic and allelic frequencies between the cases as well as controls. However upon multiple logistic regression analysis TT genotype was found to be associated with male patients  ; p = 0.12 and for TT + AT vs AA; OR-1.22 (95% CI = 0.93-1.59); p = 0.25) from the Saudi population.Results for the genotypic distribution of FABP2 is an intracellular protein expressed in the villus tips of the small intestine, has a high affinity for saturated and unsaturated long-chain fatty acids and is believed to be involved in the absorption and transport of dietary fatty acids [FABP2 gene has been suggested as a possible candidate gene in the development of IR and T2DM [FABP2 was investigated as a possible genetic factor associated with T2DM and Obesity. Studies examining the association of A54T polymorphism with IR, T2DM and Obesity are contradictory and inconclusive [FABP2 possesses a greater affinity for long-chain FA than the A allele [ty acids . The assand T2DM . A54T ponclusive . The proA allele . In addiA allele . The T aA allele  and dyslA allele . In addiA allele  and a paA allele . MoreoveA allele . We haveFABP2 A54T polymorphism with T2DM in a Saudi population. To the best of our knowledge, this is the first study investigating the association of A54T polymorphism in a Saudi population. The frequency of T allele of A54T polymorphism was 0.29 similar to Greek and Caucasian population [FABP2[In the present study we investigated the association of pulation -23. A54Ton [FABP2.FABP2 variants and T2DM. A54T polymorphism was carried out in relation to multiple diseases and the reports are summarize in Table n = 438) samples and that have not examined its association with other disease.Previous studies of A54T polymorphisms investigated lipid related diseases such as coronary artery disease (CAD) . Canani There are several studies denote no association of the T allele with T2DM -29 and oFABP2 gene and T2DM, suggesting that A54T polymorphism is not a major risk factor for the T2DM. Overall, this study indicates that A54T polymorphism could not affect directly the presence of T2DM due to the differential absorption of long chain fatty acids in the presence of the T allele. This is the first study finding the interaction between FABP2 and T2DM in Saudi population. Further functional studies as well as well-characterized larger molecular epidemiological studies are necessary to confirm our findings.In conclusion, the present study provides no evidence of any association between A54T polymorphism (rs1799883) in The authors declare that they have no competing interests.AKK and BMD were main investigator of this study. IAK has plan the study protocol, drafted the manuscript, prepared the final version of the manuscript and CA. ANM has confirmed the T2DM samples. HTN has helped in the revision of the manuscript. AMS and AFK helped with the genotyping and interpretation of the data. SR, took care about the sample collection. AYA and AMAM has participated in the study coordination and took part in the statistical analysis. All authors read and approved the final manuscript.


Recent studies have reported the association between IL-6-174G/C polymorphism and sepsis. However, the results are inconclusive and conflicting. To better understand the role of IL-6-174G/C polymorphism in sepsis, we conducted a comprehensive meta-analysis.Literature search was conducted through PubMed, Embase, Web of Knowledge databases until July 29, 2013. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effect model based on heterogeneity test in total and subgroup analyses.Twenty studies on the risk of sepsis and seven studies on sepsis mortality were included. None of the results showed evidence of a significant association between IL-6-174G/C polymorphism and sepsis risk in overall analysis or subgroup analyses based on sepsis type, ethnicity, source of control and age under any genetic model . Although there was a statistically significant association between IL-6-174 G/C polymorphism and sepsis-related mortality under the recessive model, the significance did not exist after Bonferroni’s correction.Current evidence does not support a direct effect of IL-6-174 G/C polymorphism on the risk of sepsis. In addition, there was no association between IL-6-174 G/C polymorphism and sepsis mortality after Bonferroni’s correction. Further analyses of gene-environment interactions and more studies based on larger sample size and homogeneous sepsis patients are required. Sepsis is characterized by systemic inflammatory response of the host organism to the invasion of microorganisms. Despite the advances in the development of antibiotics and clinical care, sepsis remains the leading cause of death in critically ill patients. About $16.7 billion is spent in U.S. annually for sepsis with the mortality rate of 28.6% . RecentlIL-6 is a proinflammatory cytokine secreted by monocytes, endothelial cells and fibroblasts, and is able to stimulate B and T lymphocytes and induce fever. Some studies have indicated that IL-6 may play a key role in the inflammatory response to microbial invasion. . PreviouThe human IL-6 gene is mapped to chromosome 7p21 region and contains several single nucleotide polymorphisms. The G to C polymorphism at position-174 of the IL-6 gene rs1800795) influences poor outcomes in a number of inflammatory diseases ,15. Furt00795 infA systematic literature search was conducted in PubMed, Embase and Web of Knowledge databases up to July 29 2013. The combination of terms “Interleukin-6” or “IL-6”; “sepsis” “septic shock” or “septicemia”; and “polymorphism” “variation” “mutation” or “genotype” was used without language restriction and publication date. Relevant studies were retrieved, and their references were checked to find other relevant publications. Authors were contacted to obtain related data not revealed in original articles.The inclusion criteria were: (1) evaluation of the association between IL-6–174G/C polymorphism and sepsis; (2) independent cohort or case-control studies; (3) the number or frequency of genotypes was provided in studies or obtained by contacting the authors. The exclusion criteria were: (1) studies with insufficient information, such as genotype number not reported; (2) review, comment or abstract. For studies with overlapping samples, only the one with the largest sample size was included. When an article reported the results on different ethnicities, we treated them as separate studies.Two investigators conducted the data extraction independently in order to reduce personal error and ensure the reliability. Useful information was extracted as following: first author’s name, publication year, country, ethnicity, source of control, age, sepsis type, number or frequency of cases and controls for each IL-6–174G/C genotype. Hardy-Weinberg equilibrium was tested based on provided data. Predesigned standard data forms were used for information collection. Disagreement was resolved by discussion.2 value and Chi-square based Q-test. P>0.10 for Q-test or I2 value less than 50% revealed no obvious heterogeneity across studies, allowing to use a fixed effects model (the Mantel-Haenszel method); otherwise, a random effects model was selected (the DerSimonian and Laird method). Galbraith plots were performed to investigate the source of between-study heterogeneity. Sensitivity analyses were performed through removing each study in turn to evaluate the stability of results. Publication bias was examined by Begg’s funnel plot qualitatively  and Egger’s test quantitatively. At last, Bonferroni’s correction was conducted to control the type I error rate in the meta-analysis of mortality. All statistical analyses were performed by using Revman 5.2 software  and STATA 12.0 software .Because the model of inheritance of sepsis is unknown, we conducted the meta-analysis with the allele comparison model (C vs. G), the codominant model (CC vs. GG), the recessive model (CC vs. GG/GC) and the dominant model (CC/GC vs. GG). The association between IL-6–174G/C polymorphism and sepsis was evaluated by pooled odds ratio (OR) and 95% confidence interval (CI). Z test was carried out to evaluate the statistical significance of pooled ORs. In addition to overall analyses, subgroup analyses were performed according to sepsis type (the definitions according to the ACCP/SCCM guidelines ), ethnicA total of 868 records were identified by searching three databases  and 1 record was identified through references. After excluding 289 duplications, 528 records were removed for their unmatched titles or abstracts. After reading the full text of the remaining 52 records, 32 records  were excluded. Finally, 20 records (21 studies) were included in our meta-analysis –23,27–40Eighteen records (nineteen studies) –34,36–39There were five records (six studies) –40 aboutThere was no obvious heterogeneity for overall analysis about sepsis risk except the dominant model (P = 0.03). Although subgroup analyses were conducted, the heterogeneity did not decrease effectively except for adult subgroup analysis. We explained the heterogeneity by Galbraith plot. Three studies performed by Ahrens et al. , Baier eFor sepsis mortality, obvious heterogeneity also existed under the allele comparison model and the codominant model (P = 0.01 and P = 0.05) . GalbraiSensitivity analyses were carried out in order to examine the results of our meta-analysis through removing each study sequentially. No obvious changes were found in the results, which confirmed our results were stable under the four models.Egger’s test and Begg’s funnel plot were used to evaluate publication bias quantitatively and qualitatively respectively. Slight asymmetry was found in all of the four plots . Egger’sTo date, about twenty studies have been reported to evaluate the association between IL-6–174G/C polymorphism and sepsis –23,27–40In our meta-analysis, we evaluated the association between IL-6–174G/C polymorphism and sepsis under the allele comparison, codominant, recessive and dominant model, respectively. There was no association between IL-6–174G/C polymorphism and sepsis risk. Subgroup analyses according to ethnicity, sepsis type, source of control and healthy adult control still showed no obvious association between this polymorphism and sepsis risk. There were only one study on Asians and no mutation was found in its study population. More studies in Asian population are needed to estimate the effect of IL-6–174G/C polymorphism on sepsis risk. Although a statistical association was found between IL-6–174G/C polymorphism and sepsis mortality under the recessive model , this was not maintained after Bonferroni’s correction. Meanwhile, we did not find statistical association between this polymorphism and sepsis mortality under other three models. Therefore, there was only a moderate association between IL-6–174G/C polymorphism and sepsis mortality under the recessive model. Taken together, more studies are needed to evaluate the effect of this polymorphism on sepsis mortality.The between-study heterogeneity in our meta-analysis still existed in both overall comparisons and subgroup analyses. The results revealed that studies conducted by Baier et al.  (study1)The results may be influenced by the publication bias which could make false-negative results suppressed or false-positive results magnified. Although Begg’s funnel plots were slightly asymmetrical, Egger’s test revealed no obvious publication bias for sepsis risk and mortality in our meta-analysis. Therefore, more studies were needed to verify the results of our meta-analysis. All of the results should be interpreted cautiously.Even though there were more than twenty studies in our meta-analysis, limitations in our meta-analysis should be pointed out. Firstly, the number of studies was moderate especially in subgroup analyses, thus limiting the interpretation of results in our study. Secondly, the study population in our meta-analysis focused on Europeans and Americans. Our conclusion may be not suitable for Asian. Thirdly, sepsis is a complex clinical syndrome related to systemic inflammation supposed to be generated by infection. Such a syndrome concerns very different pathogens with different virulence, different location and different sensitivity to antibiotics. All aspects above add population heterogeneity. The mortality and potentially the risk of sepsis are largely influenced by medical environment particularly the so called “co-morbidity”, such as chronic disease and resistant bacteria. However, we could not make all factors matched for the limited information, which may influence the results. Fourthly, we could not ensure the consistency in control samples of all studies, which may play a crucial role in drawing a conclusion exactly. Finally, we could not address the interactions of genes for the lack of the related information.In conclusion, the IL-6–174G/C polymorphism may not be associated with the risk of sepsis. In addition, there was no association between IL-6–174 G/C polymorphism and sepsis mortality after Bonferroni’s correction. Further analyses of gene-environment interactions and more studies based on larger sample size and homogeneous sepsis patients are required.S1 PRISMA Checklist(DOC)Click here for additional data file.


Cell adhesion molecules (CAMs) are involved in various immune-mediated diseases. This study was conducted to investigate the association of single nucleotide polymorphisms (SNPs) of CAMs with Behçet’s disease (BD) in a Chinese Han population. A two-stage association study was carried out in 1149 BD patients and 2107 normal controls. Genotyping of 43 SNPs was performed using MassARRAY System (Sequenom), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP assays. The expression of CD6 and CD11c was examined by real-time PCR and cytokine production was measured by ELISA. A significantly higher frequency of the CT genotype, and a lower frequency of the CC genotype and C allele of CD6 rs11230563 were observed in BD as compared with controls. Analysis of CD11c rs2929 showed that patients with BD had a significantly higher frequency of the GG genotype and G allele, and a lower frequency of the AG genotype as compared with controls. Functional experiments showed an increased CD11c expression and increased production of TNF-α and IL-1beta by LPS stimulated PBMCs in GG carriers of CD11c rs2929 compared to AA/AG carriers. Our study provides evidence that CD6 and CD11c are involved in the susceptibility to BD in a Chinese Han population. Uveitis is a vision-threatening intraocular inflammatory disease and a major cause of visual impairment and blindness. Behçet’s disease (BD) has been shown as the most common sight threatening uveitis entity in ChinaMigration of cells to the site of inflammation is a key event during uveitis and has been investigated previously in both animal modelsCell adhesion molecules (CAMs) are a group of proteins involved in cell binding or interaction between extracellular matrix (ECM) and cells. CAMs have been classified into four protein families: Ig (immunoglobulin) superfamily , the integrins , the cadherins (CDH), the selectins, and other uncategorized molecules. At an early stage of inflammation, leukocytes first adhere to the activated endothelium, and then infiltrate into the vessel wall, in association with an increasing expression of CAMsAn abundance of gene association studies with CAMs, including ICAM19101314192425271131322810The clinical characteristics, gender and age of the enrolled BD patients and controls are displayed in −4, OR = 1.94), whereas a decreased frequency of the C allele and CC genotype  was found  . The freas found . We wereas found .−4, OR = 1.51; Pc = 7.808 × 10−5, OR = 1.44, respectively), and lower frequencies of the AG genotype  when compared with controls  were found, whereas an increased frequency of the CT genotype was observed     . Combini = 1.45) , and tha = 0.64) .−4, OR = 1.37; AG genotype: Pc = 1.289 × 10−3, OR = 0.69; GG genotype: Pc = 6.102 × 10−4, OR = 1.46) and female patients . Likewise, the genotype and allele frequencies of rs11230563 also showed significant differences between patients and controls in both male  and female patients   . We subs = 0.60) . The CD6 = 0.60) .A stratified analysis was carried out to examine the association of rs2929 and rs11230563 with the main clinical features of BD. The main clinical features of BD included genital ulcer, skin lesions, arthritis, positive pathergy reaction and hypopyon. No significant association was found for the individual extraocular manifestations of BD with the tested SNPs  and S3.−3)  . Differe−3) .−4) carriers , integrin alpha M (CD11b), integrin alpha X (CD11c), and integrin alpha D (CD11d) chainThe association we described between the CD6 SNP rs11230563 has not yet been reported earlier in BD, although a haplotype of CD6 containing rs11230563 and rs2074225 was shown to be associated with MSCD6 is a membrane glycoprotein, which is mainly expressed on T cells. It interacts with its ligand activated leukocyte cell adhesion molecule (ALCAM/CD166), which is expressed on many cell types including nervous system cells, epithelial cells, mesenchymal cells, endothelial cells and leukocytesThe role of CD6 and ALCAM in ocular inflammatory disease has not received much attention until now, although expression of ALCAM has been described for retinal vascular endothelial cellsIt is worthwhile to point out that the odds ratios were toward different directions between the homozygotes and heterozygotes. The genotype data may be due to the dominant behavior of the A allele of rs2929 and T allele of rs11230563. In view of the relatively low frequency of the AA genotype (rs2929) and the TT genotype (rs11230563) both in patients and controls, we did not find a protective effect of the AA genotype of rs2929  or a positive predisposing effect of the TT genotype of rs11230563 .The present study has some limitations that should be noted. Firstly, though we tried to match the controls for gender, 82.9 percent of our BD cases were male, while 54.9 percent of controls were male. Analysis of our data according to gender however showed that the association between rs11230563 and rs2929 and BD was seen in both the female and male population. Secondly, our study identified rs2929 of CD11c and rs11230563 of CD6 as potential risk factors in the susceptibility for BD in a Chinese Han population, but the exact mechanism whereby these variants affect the disease pathogenesis were not clarified and deserves further study. Functional experiments showed that the CD11c risk variant influenced CD11c expression and the production of several pro-inflammatory cytokines. We only examined the effect of rs2929 in healthy genotyped controls because the BD patient population is extremely heterogeneous due to a variable inflammatory course and due to the immunosuppressive drug treatment used. Thirdly, we only chose previously reported loci in the family of adhesion molecules, which were known to be associated with autoimmune diseases and it cannot be ruled out that other SNPs in cell adhesion molecules can be associated with BD. A detailed sequence analysis of the identified risk genes should be performed to investigate whether rare variants of these factors might also be involved, thus strengthening the functional role of these factors in BD development. Last but not the least, since our BD patients were recruited from an ophthalmology department, further confirmations should be done by investigating BD patients originating from other medical fields such as the rheumatology or dermatology departments.In summary, our study showed that CD6 rs11230563 and CD11c rs2929 polymorphisms are associated with susceptibility to BD in a Chinese Han population. Further studies are needed to reveal the mechanisms whereby CD6 and CD11c expression and function are regulated in BD and whether this knowledge can be used to develop novel therapeutic approaches.From April 2008 to October 2015, 1149 BD patients, visiting the First Affiliated Hospital of Chongqing Medical University , were selected as the study population. BD patients were strictly diagnosed based upon the criteria of the International Study Group for BD2-value of LD <0.8 between adjacent markers) in 26 molecules. The SNPs tested in this study included 4 SNPs  of ICAM19101314192711313228Single nucleotide polymorphism (SNP) selection was based on previous studies on the association between cell adhesion molecules and inflammatory and autoimmune disease910111213141516171819202122232425262728293031323334® SNP Genotyping Assay  on the Applied Biosystems 7500 Real-Time PCR system in the second stage. The analysis was conducted using TaqMan® Genotyper Software. Five percent of study samples in a random fashion were sequenced directly to assure the validity of the SNP genotyping method used. The success rate of all SNPs genotyping ranged from 98.0% to 100%.Genomic DNA was extracted from venous blood samples of BD patients and healthy controls using the QIAamp DNA Blood Mini Kit . All SNPs were assayed using a matrix-assisted laser desorption/ionization time of flight mass spectrometry platform  in the first stage, following the manufacturer’s instruction. Samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for rs11230563 in the second stage. Digestion products were separated on a 4% agarose gel and stained with GoldView TM . Rs2929 (TagMan assay ID: C_9607211_10) genotypes were analyzed using the TaqMan6 cells per well) were seeded in 24-well plates and cultured in RPMI medium 1640 supplemented with 10% fetal calf serum , 100 U/ml penicillin, 100ug/ml streptomycin. In order to detect the production of IL-1beta, IL-6, IL-8, IL-10, TNF-α and MCP-1, PBMCs were cultured with 100 ng/ml lipopolysaccharide  for 24 hours.Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood samples of healthy controls by Ficoll-Hypaque density-gradient centrifugation. Isolated PBMCs  followed by reverse transcription using a transcriptase kit. The sequences of the sense and antisense primers were as follows: CD6: 5′-TGCACAATCTGTCCACTCCC-3′ and 5′-AACGATGGAGGGGATGAGGA-3′; CD11c: 5′-CCGACCATATCTGCCAGGAC-3′ and 5′-CCCGTCATTCCACACCATCA-3′. β-actin was selected as the internal reference gene and its expression was measured by the following primers: forward 5′-GGATGCAGAAGGAGATCACTG-3′ and reverse 5′-CGATCCACACGGAGTACTT-3′. The assays were performed on a 7500 real-time instrument (ABI). Relative expression levels were calculated by the 2−ΔΔCt method.The concentration of IL-1beta, IL-6, IL-8, IL-10, TNF-α and MCP-1 in PBMC culture supernatants was detected by the human Duoset ELISA development kit  based upon the manufacturer’s protocols.et al.et al.As to SNP analysis, Hardy-Weinberg equilibrium (HWE) was tested by the Chi-square test. Genotype frequencies were calculated by direct counting. Allele and genotype frequencies were compared between patients and controls by the chi-square test using SPSS version 19.0. P values were evaluated with the χ2 test or Fisher’s exact test. Genotype testing was performed by comparing one genotype versus the other two pooled together. P values were corrected (Pc) for multiple comparisons with the Bonferroni correction by multiplying with the number of analyses performed according to the methods of Jiang How to cite this article: Zheng, M. et al. Genetic polymorphisms of cell adhesion molecules in Behcet's disease in a Chinese Han population. Sci. Rep.6, 24974; doi: 10.1038/srep24974 (2016).


Egger’s test did not find any publication bias. In conclusion, our study indicated that higher category of dietary vitamin A intake could reduce the glioma risk. However, we could not do a dose-response analysis for vitamin A intake with glioma risk due to the limited data in each reported individual article. Due to this limitation, further studies with detailed dose, cases and person-years for each category is wanted to assess this dose-response association.The results from epidemiological studies between dietary vitamin A intake and glioma risk is not consistent. Thus, a meta-analysis was conducted to confirm the exact relationship between them. PubMed and Web of Knowledge were used to search the relevant articles up to May 2015. Pooled relative risk (RR) with 95% confidence interval (CI)was calculated using random-effect model. Egger’s test was used to assess the small-study effect. At the end, seven articles with eight case-control studies involving 1841 glioma cases and 4123 participants were included. Our study indicated that highest category of dietary vitamin A intake was significantly associated with reduced risk of glioma (RR = 0.80, 95% CI = 0.62–0.98,  Two rA intake . ConsideThe relevant articles were searched using the databases of PubMed  and Web vs. lowest category of dietary vitamin A intake.The following inclusion criteria were used: (1) the studies were using a prospective design or a case-control design; (2) the exposure of interest was dietary vitamin A intake; (3) the ending outcome was glioma; (4) odds ratio (OR) or relative risks (RR) and their 95% confidence intervals (CI) were available for highest category of dietary vitamin A versus lowest category of vitamin A intake. The multivariable adjustment RR (95% CI) was used from each reported study if possible.Two researchers (Wen Lv and Xian Zhong) extracted the following information from the included study independently: the last name of the first author’s, publication years, geographic locations of the study, study design, sample source, the age for cases and participants, the number of cases and person-years, and RR (95% CI) for the highest category of dietary vitamin A intake vs. lowest category for the glioma risk was pooled using a random-effects model [I2 of Higgins and Thompson [I2 described the proportion of total variation attributable to between-study heterogeneity, and I2 values of 0, 25%, 50% and 75% represent no, low, moderate, and high heterogeneity, respectively [p ≤ 0.05 was accepted as statistically significant.The multivariate adjusted RR with 95% CI for highest category of vitamin A ts model . The I2 Thompson  was usedectively . Meta-reectively . Egger’sectively . A sensiectively . If so, We identified 385 articles from all the databases, and twenty-three articles were reviewed in full after reviewing the title/abstract. Sixteen studies were further excluded from this analysis for various reasons showed in versus lowest category could reduce the glioma risk   .I2 = 54.9%, pheterogeneity = 0.030) was detected in our results. We then used meta-regression with the covariates of publication years, geographic locations where the study conducted, cases and source of controls to explore the potential heterogeneity. However, no significant finding was found in the above-mentioned analysis (the detailed results were shown in Supplement Moderate of heterogeneity (p = 0.564).Influence analysis showed that the pooled RR did not lie out of the 95% CI when we removed one individual study at a time . There ip < 0.001), but not in the other countries . Seven of the included studies were population-based case-control (PBCC) studies, and only one study was hospital-based case-control (HBCC) study. We then combined the data for PBCC studies, but not for HBCC studies. And the result was only significant in PBCC studies .In stratified analysis by geographic locations, highest category of dietary vitamin A intake could reduce glioma risk among American populations  was found. As we all know, the publication years, geographic location where the study conducted, and source of controls might arise the heterogeneity. We therefore performed meta-regression and subgroup analyses to explore the potential heterogeneity. As a result, we did not find the potential heterogeneity from the above analyses. Considering other genetic and environment variables may affect the heterogeneity, further studies with multivariate adjustment RR should assess this association.One paper had reported that heterogeneity in the meta-analysis is common , and expversus lowest level. Second, our meta-analysis included much more cases and participants; this may obtain a more reasonable result. Third, there is no significant publication bias tested by the Egger’ test. However, some limitations should be concerned in this study. First, the included studies were all case-control design. Case-control studies may suffer from recall bias and selection bias, but they are important methods in etiology research. Further studies original with prospective design and other design are wanted to confirm this result. Second, different measurement could affect the dietary intake. And the range of intake may be changed during the different measurement [et al. 1994) [et al. 1994) [et al. 1997) [Our meta-analysis had some advantages. To the best of our knowledge, we conducted the first comprehensive meta-analysis between dietary vitamin A intake and glioma risk based on highest level surement . Third, l. 1994)  stronglyl. 1994)  reportedl. 1997)  reportedl. 1997) ,28. But In conclusions, findings from this study indicated that higher category of dietary vitamin A intake could reduce glioma risk. However, dose-response analysis was not performed between vitamin A intake and glioma risk due to the limited data reported in each individual article. Due to this limitation, further studies with detailed dose, cases, and participants (or person-years) for each category is wanted to assess this dose-response association.