Objective: The exon 3-deleted/full-length (d3/fl) growth hormone receptor (d3/fl-GHR) polymorphism has been associated with responsiveness to GH therapy in some children and also with adult height variation in the general population. We aimed to evaluate the distribution of d3/fl-GHR polymorphism in a Turkish population.  Methods: The study included 477  healthy adults with a mean±SD age of 31.1±9.0 years (range: 18-57). Height and body mass index (BMI) were expressed as standard deviation score (SDS) according to national standards. All adults had normal height and BMI SDSs (between -2 and +2). GHR exon 3 isoforms were studied by simple multiplex polymerase chain reaction method. Insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) values were also  measured and expressed as SDS. Results:  The distribution of the GHR exon 3 genotypes in the Turkish  healthy adults was  35% (n=167) for fl/fl, 39% (n=186) for fl/d3, and 26% (n=124) for d3/d3. There was no difference between genders in GHR exon 3 genotypes. Frequencies of fl allele  and d3 allele were  54.5% and 45.5%, respectively. There were no differences in height SDS and BMI SDS among the three d3/fl-GHR genotype groups. There was a significant difference in IGFBP-3 SDS between fl/fl and fl/d3 groups (p=0.022). Conclusions: This study presents the results of GHR polymorphism in a Turkish population as a reference for further studies. The distribution was similiar to European populations. There were no correlations between GHR isoforms and height SDS or other clinical/biochemical characteristics of the individuals except for higher IGFBP-3 levels in the fl/d3 group as compared to the  fl/fl group. Whether this finding implies an abnormality, needs further investigation. Conflict of interest:None declared. The growth hormone insulin like growth factor-1 (GH-IGF-1) axis is the key regulator of somatic growth in humans. Adult height is controlled by genetic and non-genetic factors. Common variants in genes of  the GH-IGF-1 axis  contribute to height variation in the general population ,3,4. GHR gene is located on the short arm of chromosome 5 p13.1-p12) . It cons . It con The aim of this study was to evaluate the distribution of  GHR exon 3 polymorphisms in the Turkish population. The study included 477  healthy adults. The volunteers were recruited from blood donors and hospital staff. Mean±SD age was 31.1±9.0 years (range: 18-57). None of the subjects had received therapy with GH or any other anabolic drug. A single subject per family was included in the study. Height and weight were measured by standard methods and body mass index (BMI) was calculated as weight (kg)/height (m)2.  Height, weight and BMI were expressed as standard deviation score (SDS) ,17. Heig  IGF-1 (ng/mL) was measured by IRMA method  . The limit of sensitivity was 0.80 ng/mL. Intra and inter-assay coefficient of variation (CV)  values  were 1.5-3.4% and 1.5-8.2%, respectively. IGFBP-3 (ng/mL), also measured by IRMA method , has a limit of sensitivity of 0.5 ng/mL.  Intra and inter-assay CV were 1.8–3.9% and 0.5–1.9%, respectively. IGF-1 and IGFBP-3 SDSs were calculated using reference values of the IGF-1 and IGFBP-3 assays (http://www.beckmancoulter.com).  Subanalysis was carried out by grouping the patients according to their height SDS as the tallest (+2 and >+1), the average (≤+1 and >-1), and the shortest (≤-1 and ≥-2) height groups.Molecular AnalysisGenomic DNA was isolated from peripheral blood  leucocytes of healthy adults by DNA isolation kit  in Istanbul Faculty of Medicine at Istanbul University. The frequency of the GHR transcript variant [full length (fl) or exon 3 deleted (d3)] was tested by a simple multiplex polymerase chain reaction (PCR) assay, using one sense primer (G1) and two antisense primers one specific for GHRfl (G3) and the other specific for GHRd3 isoform (G2) (GenBank accession number AF155912), as described by Pantel et al . AmplifiEthicsThis study was approved by the local ethics committee. Written informed consent was obtained from all subjects. Statistical AnalysisStatistical analyses were done using SPSS version 12.0 . Values are expressed as mean±SD. Comparison between the means was done by parametric tests. Height SDS in the healthy adults was analyzed for normal distribution by the Kolmogorov-Smirnov test . Hardy-Weinberg equilibrium (HWE) was calculated according to standard procedures using c2 analysis.  Differences between the variables evaluated among the d3/fl-GHR genotypes were calculated using ANOVA (Bonferroni). Differences for the d3/fl-GHR genotype frequencies were analyzed by the c2 test. A p-value of less than 0.05 was considered statistically significant. The distribution of the three GHR exon 3 genotypes in this Turkish healthy adult population was  35% (n=167) for fl/fl, 39% (n=186) for fl/d3, and 26% (n=124) for d3/d3. There was no difference between genders with respect to the distribution of these three GHR exon 3 genotypes. There were also no differences in height and BMI SDSs among the three d3/fl-GHR genotype groups. IGFBP-3 SDS was significantly higher in the fl/d3 group as compared to the fl/fl group (p=0.022) Genotype frequencies reached HWE only in the tallest height group, but not in the average and the shortest height groups. In the total population, frequencies of fl allele  and d3 allele were  54.5% (n=520) and 45.5% (n=434), respectively. Allele frequencies were similar in the three height groups. There were no differences in genotypes or in IGF-1 and IGFBP-3 SDS values among subjects grouped according to their height SDS. IGF-1 SDS was found to be higher in the tallest height group, but this difference was not significant Adult height is not determined by a single gene but by complx polygenic inheritance. Studies in adult twins have shown that differences in height are related by 75-89% to genetic factors ,19. GeneStudies aiming to show the effects of GHR exon 3 genotypes on the height differences among populations revealed that the frequency of d3 allele was high among  the Caucasian population ,11,21,   In our study, the frequencies of GHR exon 3 genotypes were 35% for fl/fl, %39 for fl/d3, 26% for d3/d3. The fl allele frequency was 54.5%, while the d3 allele frequency was 45.5%.  No difference was found in the distribution of GHR exon 3 genotypes among the shortest height group (height SDS between -1 and -2) and the other groups. Neither the total group nor any  height group, except for the tallest height group, reached HWE. GHR exon 3 genotype and allele frequencies were similar to those of European adults with normal stature and the homozygous d3 genotype was slightly more frequent . Kenth et al  reported Audi et al  investigMillar et al  comparedIn our study, although there was no difference among the genotype groups in terms of BMI SDS and IGF-1 SDS, the subjects with  heterozygous GHR exon 3 polimorphism had significantly higher IGFBP-3 SDS. There was a  significant positive correlation between BMI SDS and IGFBP-3 SDS. Recent studies have assessed the  interaction between efficacy of GH therapy and GHR exon 3 polymorphisms in various groups of GH deficient (GHD) patients ,27,28. T The different results in the studies carried out in children and in adults highlight the risk of false negativity or positivity due to the interference of several factors on genotype-phenotype interactions. Only prospective and larger studies including a homogeneous group of GHD patients bearing all GHR  genotypes in a significant number, with similar inclusion and exclusion criteria as well as a similar therapeutic approach, would clarify the contribution of d3-GHR to the response to GH therapy. In conclusion, this study presents the results of GHR  polymorphism in a Turkish population as a reference for  further studies. The distribution was similar to that in European populations. There were no correlations between heights of the individuals and GHR isoforms except for a  higher IGFBP-3 in the fl/d3 group as compared to the fl/fl group.


Several epidemiological studies suggested that methionine synthase (MTRR) rs1801394 and methionine synthase reductase (MTR) rs1805087 polymorphisms may be involved in the risk of meningioma in adults; however, the results from different case-control studies have been inconsistent. Therefore, we performed a meta-analysis to investigate the association of MTRR and MTR polymorphisms with meningioma. PubMed, Web of Knowledge, China National Knowledge Infrastructure and Wanfang databases were searched up to October 30, 2013 and 3 publications, involving 7 case-control studies, were finally included. Following data extraction, a meta-analysis was conducted using Stata 12.0 software. The pooled results based on the fixed effects model demonstrated that the MTRR rs1801394 polymorphism was associated with an increased risk of meningioma ; however, an association between the MTR rs1805087 polymorphism and the risk of meningioma was not identified . Therefore, the currently available evidence suggests that the MTRR rs1801394 polymorphism may increase the risk of meningioma, whereas the MTRR rs1801394 polymorphism is not associated with meningioma. The majority of meningiomas are benign tumors located intracranially and are often associated with severe and possibly fatal consequences, although they are encapsulated and non-malignant tumors with restricted numbers of genetic aberrations . MeningiMethionine synthase (MTRR), an enzyme that catalyzes the remethylation of homocysteine to methionine and the concurrent demethylation of 5-methyltetrahydrofolate to tetrahydrofolate, is a vitamin B12-dependent enzyme. Methionine synthase reductase (MTR), which is a reductase catalyzing methyl cobalt amine regeneration, is the cofactor of MTRR and plays a vital role in maintaining MTRR in the folate metabolic process. The MTRR A66G (rs1801394) polymorphism is a well-recognized locus associated with enzyme function and may affect the interaction of MTRR and MTR, participating in tumor formation . A commoet al  the patients had been diagnosed with meningioma by magnetic resonance imaging, histological, pathological, or cytological methods; ii) the association of MTRR rs1801394 and/or MTR rs1805087 polymorphism with meningioma susceptibility was investigated; iii) the study design was a case-control study; iv) the number of individual genotypes in the case and control groups was provided or could be calculated using valid information; and v) the publication language was restricted to English or Chinese.The PubMed, Web of Knowledge, China National Knowledge Infrastructure and Wanfang databases were searched up to October 30, 2013 using the following key words: (meningioma or meningiomatosis or meningeoma or meningothelioma or durosarcoma or clear cell meningioma or sphenoid ridge meningiomas) and  and (methionine synthase or MTRR or methionine synthase reductase or MTR). The bibliographies of the included articles were hand-searched to identify relevant meta-analyses and recent reviews.Two investigators independently performed data extraction according to the pre-specified inclusion criteria. Any disagreements were resolved by consulting a third investigator. The following information were extracted: surname of the first author, publication year, country, ethnicity, source of controls, sample size, genotyping method, genotyping distribution in the case and control groups and Hardy-Weinberg equilibrium (HWE) for controls.2 statistics  and corresponding 95% confidence intervals (CIs) were calculated for five genetic models in both MTRR rs1801394 and MTR rs1805087 polymorphisms: G vs. A, GG vs. AA, AG vs. AA, (AG+GG) vs. AA and GG vs. (AG+AA). The heterogeneity among the included case-control studies was assessed using Iatistics  and the articles ; otherwiarticles . AdditioOur search strategy, initially identified 12 publications. Following removal of duplicates and non-relevant articles, 3 publications with 7 case-control studies, including a total of 1,521 meningioma patients and 1,523 healthy controls for MTR rs1805087 polymorphism and 1,231 meningioma patients and 1,237 healthy controls for MTRR rs1801394 polymorphism, were finally included ,29.Three articles involving 7 case-control studies focused on MTR rs1805087 polymorphism ,28,29 anThe meta-analysis results of the overall population based on the fixed effects model are presented in The sensitivity analysis was performed by removing each of the included studies of the meta-analysis and the results demonstrated that the ORs were not significantly altered, suggesting that the results were statistically robust and credible.The publication bias was assessed with the Egger’s linear regression test  and therFolate metabolism gene polymorphisms have been implicated in the pathogenesis of meningioma and numerous studies have evaluated the association between the two. Evidence from a previous meta-analysis  demonstrThe overall result of the present meta-analysis, based on 6 case-control studies ,28 focusThe aggregated results of our study, based on 7 case-control studies ,28,29 onThere were certain limitations to our meta-analysis. First, the sample size was the most important limiting factor, as the included studies were relatively small. Second, ethnicity played an important role, as we found that the MTRR rs1801394 polymorphism may increase the susceptibility to meningioma in four genetic models, except the AG vs. AA model, whereas we observed that only two genetic models exhibited an association between the MTRR rs1801394 polymorphism and meningioma in Caucasian and Asian populations. This may be the most important confounding factor in our meta-analysis and the results must be interpreted with caution. Third, due to the limited number of included studies, we were unable to perform subgroup analyses according to the classification of meningioma between single-nucleotide polymorphisms and meningioma to assess the dose-response. Finally, our meta-analysis was based on unadjusted estimates, similar to all meta-analyses of polymorphisms, due to the lack of original data from the included studies. Therefore, the investigation of gene-gene and/or gene-environment interactions was restricted.In conclusion, the present meta-analysis, based on 1,521 meningioma patients and 1,523 healthy controls for MTR rs1805087 polymorphism and 1,231 meningioma patients and 1,237 healthy controls for MTRR rs1801394 polymorphism, demonstrated that the MTRR rs1801394 polymorphism is associated with an increased risk of meningioma, whereas the MTR rs1805087 polymorphism is not associated with meningioma. However, a definitive conclusion cannot be reached due to the limitations of our meta-analysis. Therefore, further large-sample size studies are required to determine the true association between these two single-nucleotide polymorphisms and meningioma in different ethnicities.


ADRB2 gene. In contrast, in CF, little is known about the response to the BD and the association of CF´s severity with the different polymorphisms in ADRB2 gene. In this context, our objective was to verify whether the Arg16Gly and Glu27Gln polymorphisms in ADRB2 gene are associated with severity and with the bronchodilator response in CF patients.The most common cystic fibrosis (CF) manifestation is the progressive chronic obstructive pulmonary disease caused by deficiency, dysfunction, or absence of the CFTR (Cystic Fibrosis Transmembrane Regulator) protein on the apical surface of the cells in the respiratory tract. The use of bronchodilators (BD), and inhaled corticosteroids (IC) have been suggested for the management of airway inflammation in CF. The effectiveness of BD and IC have been verified, proven in laboratory and in the clinical treatment for asthma patients. However, in CF, the effectiveness of these drugs is controversial. The extent of asthma’s response to BD depends on the presence of polymorphisms in the CFTR gene, polymorphisms in ADRB2 gene, along with clinical and laboratorial characteristics of severity.Cross-sectional study of 122 CF patients subjected to analysis of mutations in the ADRB2 gene was associated with pancreatic insufficiency(p:0.009), Bhalla score(p:0.039), forced expiratory volume in the first second[FEV1(%)](p:0.003), forced expiratory flow between 25 and 75% of the forced vital capacity-FVC[FEF25-75(%)](p:0.008) and lower age at the first isolation of the Pseudomonas aeruginosa(p:0.012). The response to the BD spirometry was associated with clinical severity markers, FEV1(%)(p:0.011) and FEF25-75(%)(p:0.019), for the Arg16Gly polymorphism in the ADRB2 gene. The haplotype analysis showed association with the FEV1/FVC marker from the spirometry test, before and after using the BD, with higher values in the group with Gly/Gly and Glu/Glu, respectively, for the Arg16Gly and Gln27Glu polymorphisms. The analysis by MDR2.0 software, showed association with FEF25-75%; the response to Arg16Gly was respondent by 17.35% and Gln27Glu by 6.8% in variation found.The Arg16Gly polymorphism in ADRB2 gene with CF´s severity and bronchodilator response.There was an association between the Arg16Gly and Gln27Glu polymorphisms in  Studies have confirmed the mechanisms though which cystic fibrosis (CF) patients with similar mutations show significantly different signs and symptoms -4. Even Unlike most patients with asthma, the inflammation in CF is predominantly neutrophilic , with anADRB2 gene . The project was approved by the University Ethics Committee (#528/2008), all patients and/or their guardians signed an informed consent.A cross-sectional study was conducted in a referral center for CF treatment, at the Campinas University Hospital (UNICAMP) in 2010 and 2011. A total of 122 patients were included, with at least seven years of age and who underwent pulmonary function tests before and after the use of inhaled Albuterol (400 mg) according to the American Thoracic Society (2011) . The pat2 formula was used; for the remaining patients the WHO ANTHRO PLUS (children 7-19 years old)  and 2 GG [Gly/Gly + Glu/Glu ]. In the study by Hart et al. (2005) [1 marker. And the values of 4.4 (± 5.8), 7.9 (± 8.7) and 9.0 (± 5.8); respectively to 0 GG (N = 27), 1GG (N = 64) and 2GG (N = 15), with p values equal to 0.033, 0.027 and 0.305; respectively for the models, additive, dominant and recessive.In the haplotypes analysis the Ar/Arg + Gln/Gln presence was associated with the best response to Bronchodilation for the marker FEV. (2005) , the hapIn our results, the bronchodilator response was reduced with the presence of the variants with Gly or Glu allele, a fact contrary to that reported by Hart et al. (2005) .Possible limitations of our study included: sample size, different age groups, and different severities of lung disease that could express differences in the BD response.2-AR protein and the clinical markers of CF´s severity, and others studies about the large macromolecular complex are necessary to improve knowledge about the interaction of the proteins on the bronchial epithelial surface.Our data can provide better understanding about the association between polymorphism associated with βADRB2 gene genotype in the CF. Arg16Gly and Gln27Glu polymorphisms are associated with the response to the Bronchodilation. For the spirometry and other clinical variables of severity; the Arg16Gly polymorphism showed statistically significant association; diversely, the Gln27Glu showed no association. The Arg/Arg genotype to Arg16Gly polymorphism was associated with a better spirometry to FEV1(%) and FEF25-75% clinical markers and minor risk to PI, in comparison with other genotypes. To bronchodilator response the haplotype data to the polymorphism show association with positive response to beta 2 agonists to absence of genotypes Gly16Gly and Glu27Glu to FEV1/FVC(%) marker.The influence of polymorphisms in the CF´s severity and bronchospasm response is controversial in the scientific literature, and seldom studied. Our results support the idea that differences in the degree of airway responsiveness to the BD may be associated with the CFTR genotype for the mutation classes I, II and/or III; also patients with the same degree of change in the spirometry test to analyze the response to Bronchodilation.We must pay attention to the need for more studies; with the suppressed polymorphisms and their association with the clinical severity variables using a larger number of CF´s patients with the same The authors declare that they have no competing interests.FALM: made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; involved in drafting the manuscript or revising it critically for important intellectual content. CSB: carried out the molecular genetic studies and drafted the manuscript. AFR: has been involved in drafting the manuscript or revising it critically for important intellectual content. JDR: has given final approval of the version to be published. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/12/50/prepub


CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups.Several genetic studies have implicated the Rs1006737 was genotyped in 250 individuals , all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group.In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups.CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.These results indicate that  CACNA1C  gene variants. The CACNA1C SNP rs1006737 was first found to be associated with BD in a combined analysis of two GWA study datasets (P = 3.15×10−6) CACNA1C SNP was significantly associated with BD in the combined sample of 4,387 BD cases and 6,209 healthy controls  CACNA1C and schizophrenia (SZ) Despite the high heritability estimates for bipolar disorder (BD), the molecular genetic and neurobiological mechanisms for this disorder remain poorly understood. However, recent genome-wide association (GWA) studies with substantially more statistical power than former psychiatric genetic studies have provided evidence for new and promising candidate genes CACNA1C is located on chromosome 10 and encodes an alpha-1 subunit of a voltage-dependent calcium (Cav1.2) channel. Cav1.2 channels can be found in cardiac smooth muscle, neuronal and endocrine cells, where they have a variety of functions including excitation-contraction coupling, endocrine secretion and regulation of neuronal Ca2+ transients, enzyme activity and transcription CACNA1C have been found to lead to Timothy syndrome, a lethal disorder consisting of somatic symptoms like cardiac arrhythmia, and psychiatric symptoms like autism and cognitive disability Emotional dysregulation is part of the clinical phenotype of BD and SZ, manifesting as mood swings as well as affect flattening. Morphometric studies point to structural abnormalities within the medial temporal lobe, which may cause altered responsivity to emotional stimuli among these patients. In particular, the amygdala has been extensively studied in BD. In a recent meta-analysis of 321 patients with bipolar I disorder and 442 healthy controls, amygdala volume was found to be greater in patients treated with lithium compared to controls and patients not treated with lithium CACNA1C SNP rs1006737 and amygdala activity. In a study of 64 healthy individuals, carriers of the risk allele (AA/AG) had increased activity in the right amygdala in a monetary reward paradigm CACNA1C SNP rs1006737 affects amygdala activity during different paradigms related to limbic system functioning.With regards to the potential involvement of BD risk genes in limbic system dysregulation, there are reports of an association between CACNA1C was one out of three common genes for BD and SZ CACNA1C has not been investigated with fMRI in individuals suffering from SZ. But a recent study of healthy controls found increased activity in the prefrontal cortex during executive cognition in CACNA1C risk allele carriers, a finding which could imply inefficient prefrontal functioning as a genetically conditioned mechanism underlying SZ Interestingly, two recent meta-analyses reported that Taken together, it remains unclear whether the effect of this gene on amygdala activity during emotional processing is general or confined to one or more diagnostic categories.CACNA1C SNP rs1006737 risk allele. Secondarily, we aimed to determine the specificity of such associations, by testing for potential differences between healthy controls and patients with BD or SZ. Therefore, we measured fMRI amygdala blood-oxygen-level dependence (BOLD) responses during a faces matching paradigm The primary aim of the current study was to test for altered amygdala activity in carriers of the The total number of individuals in this study was 250, including 66 BD cases, 61 SZ cases and 123 healthy control subjects. All participants were of Northern European origin , part of the ongoing TOP (Thematic Organized Psychosis) Study, and included from 2003 to 2009.To be included in the study, patients had to be between 18 and 65 years, have a DSM-IV diagnosis of a bipolar spectrum or schizophrenia spectrum disorder, and be willing and able to provide written informed consent. Exclusion criteria were an IQ score below 70 and reporting a history of head injury or neurological disorder. In the healthy control group, we also excluded subjects if they or their close relatives had a lifetime history of a severe psychiatric disorder . Subjects with a history of a medical condition potentially interfering with brain function , and an illicit drug abuse/addiction diagnosis were also excluded.Patients were recruited from psychiatric in- and out-patient hospital units in the Oslo area, and had been diagnosed with bipolar I disorder (N = 30), bipolar II disorder (N = 32), bipolar disorder not otherwise specified (N = 4), schizophrenia (N = 48), schizoaffective disorder (N = 9) or schizophreniform disorder (N = 4), according to DSM-IV using the Structural Clinical Interview for DSM-IV (SCID) On the day of scanning, patients underwent an abbreviated re-interview including Young Mania Rating Scale (YMRS) The healthy control subjects were randomly recruited from the same catchment area as the patients, and underwent an initial interview where demographic and clinical information was obtained. Clinical assessment of the patients and healthy controls participating in the TOP study is described in details in a previous report Carriers of the risk allele did not differ significantly from the GG homozygotes with respect to demographical variables within the total sample or any of the diagnostic groups . FurtherThe Norwegian Scientific-Ethical Committees and the Norwegian Data Protection Agency approved the study. All subjects have given written informed consent prior to inclusion into the project.CACNA1C SNP rs1006737 was genotyped in the 250 subjects participating in this study using Affymetrix Gene Chip Genome-Wide SNP 6.0 array , as described in details elsewhere http://pngu.mgh.harvard.edu/purcell/plink/) Genomic DNA was extracted from whole blood. A widely used and validated paradigm was employed to elicit amygdala reactivity MRI scans were acquired on a 1.5 T Siemens Magnetom Sonata scanner  supplied with a standard head coil. Volumes  covering the whole brain were acquired in the axial plane, using a BOLD EPI sequence . The first seven volumes were discarded. Prior to BOLD fMRI scanning, a sagittal T1-weighted 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE) scan  was collected for better localization of functional data.http://www.fil.ion.ucl.ac.uk/spm) implemented in MATLAB7.1 . All of the functional images were realigned to the first image in the time series to correct for head motion All fMRI volumes were preprocessed and analysed with Statistical Parametric Mapping (SPM2)  with the corresponding activity in carriers of the protective allele (GG), using sex, age, diagnostic category  and medication status as covariates. Medication status was dichotomised for each of the categories Antipsychotics, Lithium, Antidepressants, Anticonvulsives and Hypnotics. We tested for potential specific effects in each diagnostic group  and phenotypic subcategory , for genotype×diagnosis interactions, and for effect of diagnostic category on amygdala activity. Findings were regarded as significant if they obtained a small volume corrected Family-Wise Error (FWE) P-value below 0.05 within the respective ROI .Statistical analyses of behavioural, sociodemographic and clinical data were performed with IBM SPSS Statistics version 19.0.Genotype group and diagnosis did not influence the accuracy rate significantly. The mean response time (RT) was significantly longer for individuals in the BD group (RT = 1255 milliseconds (ms)) and SZ group (RT = 1231 ms) than those in the healthy control group (RT = 1065 ms) (P<0.001), but did not differ significantly with respect to genotype group. For details, see CACNA1C SNP rs1006737 risk allele (AA/AG) showed significantly increased activation in the left amygdala , with an FWE-corrected P-value of 0.026. The risk allele was also significantly associated with enhanced activity in the left amygdala  in the BD group (FWE-corrected P = 0.041). There were also AA/AG associated increased activations in the right amygdala in the total sample  and in the BD group , but these did not reach FWE-corrected significance level. There were no FWE-corrected significant findings in SZ individuals or healthy controls, but the activation patterns had the same direction in all diagnostic groups for the most significant voxel in the total sample  as well as SZ  CACNA1C polymorphism and BD and SZ. One of these studies found that healthy risk allele carriers had elevated hippocampus activity during emotional processing, and increased activity in the prefrontal cortex during executive cognition Interestingly, recent GWA studies found the presently investigated SNP to be significantly associated with BD Click here for additional data file.Table S2Results for the effect of CACNA1C SNP rs1006737 (AA+AG>GG) interaction with diagnostic category on amygdala activation. Abbreviations: BD, bipolar disorder; SZ, schizophrenia; CTR, healthy controls; BDI, bipolar I disorder; BDII, bipolar II disorder; FWE, Family-wise error rate; n.s., non-significant. Only nominally significant results  are shown.(DOC)Click here for additional data file.Table S3Results for CACNA1C SNP rs1006737 (AA+AG>GG) effect on amygdala activation in phenotypic subcategories. Abbreviations: BD, bipolar disorder; BDI, bipolar I disorder; BDII, bipolar II disorder; FWE, Family-wise error rate; n.s., non-significant. Only nominally significant results  are shown.(DOC)Click here for additional data file.Figure S1Parameter estimates for diagnostic and genotype groups for CACNA1C SNP rs1006737 effect on amygdala activation. Parameter estimates for the contrast AA+AG>GG in the voxel with highest activation  in the total sample (N = 250) in different diagnostic and genotype groups. Prot = GG genotype group. Risk = AA+AG genotype group. Abbreviations: BD, bipolar disorder; SZ, schizophrenia; CTR, healthy controls.(DOC)Click here for additional data file.


ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light. Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. However, a series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism  and cancer susceptibility generated conflicting results.Excision repair cross complementing group 5 , nor in further stratified analyses by cancer type, ethnicity, source of controls and sample size. In the genotype-phenotype correlation analysis from 270 individuals, we consistently found no significant correlation of the Asp1104His polymorphism with ERCC5 mRNA expression.To derive a more precise estimation of the association between the ERCC5 Asp1104His polymorphism may contribute to individual susceptibility to cancer risk.This meta-analysis suggests that it is unlikely that the  ERCC1, XPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB1, XPF/ERCC4, and XPG/ERCC5) in the NER pathway play vital roles in repairing DNA damage and maintain genome integrity Exposure to environmental carcinogens can cause different types of DNA damage that subsequently lead to carcinogenesis of different tissues, if left unrepaired. During the evolution, humans have developed a versatile DNA repair machinery to ensure genome integrity in response to the insults of cancer-causing agents. DNA repair is a complex biological process consisting of several distinct pathways. To date, more than 150 human DNA repair genes have been identified in five major pathways: nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), double-strand break repair (DSBR), and transcription coupled repair (TCR). Of those pathways, NER is the most studied DNA repair mechanism responsible for various types of DNA damage, including thymidine dimers, oxidative DNA damage, bulky adducts cross-links, and alkylating damage ERCC5) gene, also known as the xeroderma pigmentosum group G (XPG) gene, is a member of the flap structure-specific endonuclease 1 (FEN1) family and encodes a protein of 1186 amino acids. The primary structure of human ERCC5 protein harbors the N- and I-nuclease domains that are highly conserved, which together form the nuclease core The excision repair cross complementing group 5 , Cockayne syndrome (CS), and tri-chothiodystrophy (TTD), underscore the biological importance of this gene As a structure-specific endonuclease and also a 5′-3′ exonuclease, the ERCC5 protein is required for two sub-pathways in NER. One is TCR, which preferentially removes DNA damage in the transcribed DNA strand of active genes; the other is global genomic repair (GGR), which removes lesions throughout the genome ERCC5 gene is located on chromosome 13q22-q33, consists of 15 exons that range from 61 to 1074 bp and 14 introns that range from 250 to 5763 bp, and spans 32 kb ERCC5 coding region have been identified (http://www.ncbi.nlm.nih.gov/SNP/), and 24 SNPs in the gene region have been studied for their association with cancer risk (Table S1), of which only four were nsSNPs . For example, the Asp1104His polymorphism (rs17655 G>C) is common [minor allele frequency (MAF) >0.05] and regarded as a tagger, which was most frequently investigated for its association with cancer risk. Interestingly, relatively few nsSNPs are present in the eight NER core genes, suggesting the conservativeness of these genes for their biological importance.The Table S2), but no published meta-analysis has summarized all reported studies of the Asp1104His polymorphism in association with risk of all cancer types. It is biologically plausible that the Asp1104His polymorphism, causing a change from aspartate to histidine at codon 1104 in ERCC5 protein, may result in an alteration of the gene function, thus likely altering risk of developing cancers, possibly following a recessive genetic model.In a published meta-analysis, a total of 12 SNPs of the eight NER core genes, including 6 nsSNPs, have been investigated for the associations with cancer risks ERCC5 Asp1104His polymorphism and cancer risk, the evidence regarding the role of SNPs of the ERCC5 gene as a genetic marker for cancer risk is conflicting, partially because of the possible lack of a main effect of the SNP on risk of any single type of cancer, a possibly low penetrance or weak effect, or the relatively small sample size in each of published studies. Therefore, we performed a meta-analysis to identify statistical evidence for an association between the ERCC5 Asp1104His polymorphism and cancer risk using all published data to date.To date, although a number of studies have been performed to investigate the association between the ERCC5” or “XPG”, “DNA repair”, “polymorphism” or “variant”, “case-control”, “risk”, “association”, and “cancer” or “carcinoma” or “neoplasm” or “malignance” . References of the retrieved articles or reviews on this topic were also manually screened for additional relevant eligible studies.We searched two electronic databases (MEDLINE and EMBASE) for all relevant articles with the following terms: “We defined inclusion criteria as follows: written in English or Chinese; case-control design; sufficient information for estimating odds ratio (OR) and their 95% confidence interval (CI); observed genotype frequencies in the controls in agreement with Hardy-Weinberg equilibrium (HWE). Abstracts and unpublished reports were not considered. Investigations in subjects with family history or cancer-prone disposition were also excluded. Meanwhile, if studies had overlapping subjects, we selected the most recent study that included the largest number of individuals in the publications. Additionally, we also checked for minor allelic frequency (MAF) among studies by different genotype frequencies in ethnic groups based on Hapmap or dbSNP frequencies reported for the different ethnic groups, and the datasets were excluded if they had a very high probability of inaccurate reported.ERCC5 Asp1104His (rs17655) in cases and controls, and main findings. For studies including subjects of different ethnic groups, we extracted data separately for each ethnic group and categorized as Caucasian, Asian, African and others. When a study did not state what ethic groups were included or if it was impossible to separate participants according to the data presented, we termed the sample as ‘others’.Two investigators (Zhu ML and Wang MY) independently extracted the following information from each study: the first author, year of publication, country of origin, ethnicity, cancer type, source of controls , genotyping method, number of genotyped cases and controls, numbers of genotypes for http://www.sanger.ac.uk/humgen/hapmap3) ERCC5 mRNA expression levels from EBV-transformed B lymphoblastoid cell lines from the same 270 HapMap individuals were available online (http://app3.titan.uio.no/biotools/tool.php?app=snpexp) as well ERCC5 mRNA expression for different populations.We provide biological plausibility of the studied SNP, we downloaded the Asp1104His genotyping data from the HapMap phase II release 23 data set consisting of 3.96 million SNP genotypes from 270 individuals from four populations  . In addition, we performed stratification analyses by cancer type , ethnicity, source of controls, study design and sample size .We assessed the association between the P<0.10. Values from single studies were combined using models of both random effects (DerSimonian and Laird method 1986) P value of the heterogeneity test was >0.10, the fixed-effects model was used, which indicates no significant heterogeneity of the effect size across all studies; otherwise, the random-effects model was more appropriate, which tends to provide wider CIs, when the results of the constituent studies differ among themselves. To evaluate the effect of individual studies on overall risk of cancers, we conducted sensitivity analyses by excluding each study individually and recalculating the ORs and 95% CI. We also used the inverted funnel plot and the Egger’s test to examine the potential influence of publication bias  P values were two-sided with a significance level of 0.05, unless specified otherwise.We evaluated the between-study heterogeneity by using the Chi square-based Q-test, which was considered significant if . These 49 studies included 9 breast cancer studies, 8 skin cancer studies, 5 lung cancer studies, 5 bladder cancer studies, 3 head and neck cancer studies, 3 colorectal cancer studies, 3 non-Hodgkin lymphoma studies, and 13 studies of other cancers. Of these, there were 27 hospital-based studies, 20 population-based studies, 1 family-based study, and 1 study with mixed controls. In addition, 29 of 49 studies were conducted in Caucasians, 4 were conducted in African-Americans, 6 were conducted in Asians, and the remaining 10 were conducted in other ethnic groups. Several genotyping methods were used, including the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), which was the most frequently used method, TaqMan, sequencing, Illumina, SNaPshot, SNPlex and Mass spectrometry, but two publications did not provide information about genotyping methods. Additionally, all studies were in keep with HapMap or dbSNP frequencies reported for the different ethnic groups (Table S3).We identified a total of 74 relevant publications after initial screening. Among these, 62 publications had met the inclusion criteria and were subjected to further examination. We excluded 8 publications because they did not present detailed genotyping information ERCC5 Asp1104His polymorphism and overall cancer risk under the recessive genetic models: His/His vs. Asp/Asp: OR = 0.99, 95% CI: 0.92–1.06 or His/His vs. Asp/His + Asp/Asp: OR = 0.98, 95% CI: 0.93–1.03.When all eligible studies were pooled into one dataset for the meta-analysis, we found no statistical association between the , In the stratified analysis by ethnicity, we did not observe any association between the polymorphism and cancer risk in the recessive genetic models, neither and had the similar results in the stratified analyses by tumor type, source of controls, and sample size in cases . In the sensitivity analyses, the influence of each study on the pooled OR was checked by repeating the meta-analysis while omitting each study, one at a time. This procedure validated the stability of our results. Furthermore, the inclusion of 7 studies, whose genotype distributions among the controls deviated from HWE, affected between-study heterogeneity for His/His vs. Asp/Asp , but did not influence the result of the meta-analysis significantly: His/His vs. Asp/Asp: OR = 1.00, 95% CI: 0.93–1.09. His/His vs. Asp/His + Asp/Asp: OR = 0.98, 95% CI: 0.93–1.03.There were no between-study heterogeneity among overall studies of the Figure S3), suggesting that there was no obvious publication bias. Furthermore, the Egger’s test further provided statistical evidence that there was no significant publication bias in this meta-analysis .We conducted Begg’s funnel plot and Egger’s test to access the publication bias of all included studies. The shape of the funnel plot seemed symmetrical (ERCC5 mRNA expression for Europeans (P trend = 0.308), Asians (Ptrend = 0.091) and Africans (Ptrend = 0.308)  for common diseases including cancers based on common SNPs, which are similar to our results. This is a challenge to the theory of common variants and common diseases DNA repair deregulation is a crucial factor in the multistep process of carcinogenesis, and the ERCC5 polymorphism to be a deleterious substitution http://compbio.cs.queensu.ca/F-SNP/), such a potentially functional relevance have not been validated experimentally to date. Diversities of variant-related risk associations in various kinds of cancer may result from different mechanisms of carcinogenesis among different cancer types. Although some studies have discovered some sequence variants in the region of chromosome 5p15.33 and 8q24 that are associated with risk of different cancer types Furthermore, we did not observe biological evidence for the effect of this SNP on the gene expression in terms of mRNA levels, which biological support for the result of no association. Although a sequence homology-based tool predicted this It would be hard to interpret results, if significant heterogeneity were present. However, in this meta-analysis, we did not find any obvious heterogeneity and publish bias across studies. Nevertheless, some limitations should be addressed. Firstly, although funnel plot and Egger’s test show no publication bias, selection bias could have occurred because only studies published in English and Chinese were included. Secondly, because the reference groups were not uniformly defined, some selected population-based controls and some used hospital-based cancer-free controls, non-differential misclassification bias is possible; in addition, some control groups may not be representative of the general population. Thirdly, our results were based on unadjusted OR estimates, because not all published studies presented adjusted ORs or when they did, the ORs were not adjusted by the same potential confounders, such as age, sex and exposure variables. Thus, more comprehensive individual datasets are needed to allow for the adjustment by some co-variants and further evaluation of potential gene-environmental interactions for susceptibility to cancer. Fourthly, although the sample size of our study was relatively large, the statistical power was still limited in the analyses of subgroups with small sample sizes, particularly when the effect size is small. Therefore, studies with larger sample sizes with sufficient large subgroups should be undertaken to validate our findings.ERCC5 Asp1104His polymorphism appeared to be unlikely to confer susceptibility to cancers. Further well-designed studies with larger sample sizes will be necessary to validate the findings in the present meta-analysis.In summary, our meta-analysis shows that the Figure S1ERCC5 gene map labeled with nine SNPs have been studied for associations with cancer risk. (A) Six SNPs are located in the coding region, among which four are nsSNPs, of which two are synonymous SNPs; two SNPs are located in the 5′ untranslated region, and one SNP is located in the 3′ untranslated region; six SNPs are tagging SNPs. (B) Nine SNPs with a minor allelic frequency in different populations obtained from the dbSNP database.(TIF)Click here for additional data file.Figure S2Flow chart of included studies for this meta-analysis.(TIF)Click here for additional data file.Figure S3Funnel plot analysis to detect publication bias for ERCC5 Asp1104His under the recessive genetic models  for all 44 studies. Each point represents an individual study for the indicated association.(TIF)Click here for additional data file.Table S1Summary of 24 SNPs of the ERCC5/XPG gene that have been studied for their associations with cancer risk.(DOCX)Click here for additional data file.Table S2Summary of Studied SNPs in the eight NER genes reviewed in all published meta-analysis.(DOCX)Click here for additional data file.Table S3Characteristics of the 44 references included in the meta-analysis for ERCC5 Asp1104His.(DOCX)Click here for additional data file.


TFR2 gene and AMD. A total of 493 AMD patients and 171 matched controls were genotyped for the two polymorphisms of the TFR2 gene: c.1892C>T (rs2075674) and c.−258+123T>C (rs4434553). We also assessed the modulation of some AMD risk factors by these polymorphisms. The CC and TT genotypes of the c.1892C>T were associated with AMD occurrence but the latter only in obese patients. The other polymorphism was not associated with AMD occurrence, but the CC genotype was correlated with an increasing AMD frequency in subjects with BMI < 26. The TT genotype and the T allele of this polymorphism decreased AMD occurrence in subjects above 72 years, whereas the TC genotype and the C allele increased occurrence of AMD in this group. The c.1892C>T and c.−258+123T>C polymorphisms of the TRF2 gene may be associated with AMD occurrence, either directly or by modulation of risk factors.Oxidative stress is a major factor in the pathogenesis of age-related macular degeneration (AMD). Iron may catalyze the Fenton reaction resulting in overproduction of reactive oxygen species. Transferrin receptor 2 plays a critical role in iron homeostasis and variability in its gene may influence oxidative stress and AMD occurrence. To verify this hypothesis we assessed the association between polymorphisms of the  Age-related macular degeneration is the leading cause of irreversible vision loss among elderly in the developed world and accounts for about half of all newly registered blindness cases. At the advanced stage AMD develops to one of two clinically distinct forms—dry or wet . The dryOxidative stress plays a major role in AMD pathophysiology . The retPost mortem studies showed a higher concentration of iron in RPE layer and Bruch's membrane in AMD subjects than in non-AMD individuals [The presence of free iron ions may enhance the level of oxidative stress through the Fenton reaction, which requires hydrogen peroxide, produced in the cell in several physiological processes . Post moividuals . Similarividuals .TF and TFR2 genes was found to be associated with AMD [TFR2 is also involved in nontransferrin bound-iron uptake and plays an important role in iron homeostasis regulation [TFR2 were reported to influence iron homeostasis leading to iron overload disease—hemochromatosis type III [TRF2, an important gene of iron metabolism, may influence the extent of oxidative stress and play a role in AMD pathogenesis. In the present work we checked for the association between two polymorphisms of the TRF2 gene: c.1892C>T (rs2075674) and c.–258+123T>C (rs4434553) and AMD as well as modulation of this association by some AMD risk factors.Cells absorb most of iron through the cooperation of transferrin (Tf) and its receptors 1 and 2 (TfR and TfR2) . An elevwith AMD . TFR2 isgulation , 11. Mortype III . The asstype III . It is ttype III . TherefoSix hundred two individuals were enrolled in this study: 493 AMD patients (311 in wet form of the disease and 182 in its dry form) and 171 controls. The control group comprised of age- and sex-matched individuals routinely examined with clinically excluded AMD and other retinal diseases. No one patient reported any genetic disease. Every patient was subjected to an ophthalmic examination, including best-corrected visual acuity, intraocular pressure, slit lamp examination, and fundus examination, performed with a slit lamp equipped with either noncontact or contact fundus lenses. Diagnosis of AMD was confirmed by optical coherence tomography (OCT) and, in some cases, by fluorescein angiography (FA) and indocyanine green angiography (ICG). OCT evaluated retinal thickness, the presence of RPE atrophy, drusen, or subretinal fluid and intraretinal edema; angiography assessed the anatomical status of the retinal vessels and the presence of choroidal neovascularization and leakage. The criteria for patients' selection were based on the clinical usefulness; dry form corresponded to AREDS category 2, 3, and 4 (geographic atrophy subtype) while wet form to AREDS category 4  . The OCTGenomic DNA was obtained from peripheral blood samples with the use of AxyPrep Blood Genomic DNA Miniprep kit (Axygen Biosciences) with all the steps performed according to the manufacturer's protocol. Samples of DNA were frozen at −20°C until use.2, and 1.25 U Taq polymerase (Biotools) in PCR reaction buffer . The sequences of primers are shown in  MspA1I (Fermentas)  was used. Reaction tubes contained genomic DNA, polymerase buffer, 0.25 μM of each primer  (Sigma-Aldrich), 0.5 μM dNTPs, 1.5 μM MgCl2, 1 U/μL polymerase (BIOTOOLS B&M Labs), and H2O. Sequences of primers and lengths of DNA fragments are shown in Genotyping of the c.1892C>T polymorphism was performed with restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). The reaction tube contained genomic DNA, 250 nM of each primer, 50 nM dNTP mix, 1.5 mM MgClrmentas)  and the rmentas) . For the‒20°C). Before use samples were centrifuged at 12 000 ×g for 15 min. Serum iron level has been determined by QuantiChrom Iron Assay kit (Bioassay Systems) according to the manufacturer's protocol. The absorbance was read at 450 nm.Venous blood samples were collected and centrifuged. Serum samples were portioned and stored frozen , sex, living environment , smoking status (never/former/current and never/moderate/heavy), and BMI (<26/26–30/>30). Multiple logistic regression analyses were run to test the association of genotypes and environmental and social factors with AMD occurrence. To establish polymorphism influence on AMD form progression (wet/dry), the OR analysis was performed between both groups. The serum iron level was compared between AMD and control group using Mann-Whitney rank sum test. To assess the potential association between genotypes of polymorphisms and the iron level the 1-way ANOVA analysis was performed. Statistical analysis was performed using Statistica 9.0 package (Statsof).Hardy-Weinberg equilibrium (HWE) was checked using the TFR2 gene: c.1892C>T and c.–258+123T>C in controls and AMD patients as well as in the group with the dry and wet forms of AMD. We found that the CC genotype of the c.1892C>T polymorphism was negatively correlated with the incidence of AMD , and environment of living  . We foune of AMD . We did e of AMD , wherease of AMD . Moreovee of AMD . Next, we of AMD . We did TFR2 gene expression may result in cellular damage directly related to oxidative stress [An exceptionally high metabolism rate in the retina together with the highest oxygen consumption and oxygen tension makes this organ especially prone to oxidative stress . Moreovee stress , 26.TFR2, which may have a phenotypic manifestation. The c.1892C>T polymorphism is a synonymous change p.Ala617. Using open-access SNP annotation tools we assessed that this change may be involved in splicing regulation—a T variant may create the site for exonic splicing repressor (hnRNP-H) binding [TFR2 expression [ex definitione key risk factor for AMD, also positive family history was independently associated with AMD occurrence, and this is consistent with numerous previous reports, suggesting a strong genetic basis of AMD. Unexpectedly, we found no correlation between AMD and smoking status, although we speculate that this association may fall beyond the sensitivity threshold of our experiment, mainly because of not enough number of smoking-positive responses in the questionnaire. Next, we performed an OR analysis to search for a direct association between genotypes and alleles of the polymorphisms and AMD occurrence. We found no association between c.–258+123T>C and AMD occurrence. For the c.1892C>T polymorphism we found that the common variant CC may be associated with a lower frequency of AMD occurrence, although this association was significant in crude OR only, and becomes nonsignificant after adjusting for age and sex. Therefore, this association remains uncertain and requires further analysis. Moreover, the minor, T/T, variant of the c.1892C>T polymorphism may have protective role among individuals with BMI above 30. We observed also a protective effect of the CC genotype of the c.–258+123T>C polymorphism in the subgroup of low BMI value (<26). Overweight and obesity are often reported to play a role in AMD pathogenesis [We chose two polymorphisms in  binding . The oth binding , which ipression . We founogenesis . AnotherTFR2 gene may play a role in the modulation of AMD risk. We reported the interaction effect between polymorphisms of the TFR2 gene with BMI and age. These results suggest an important role of iron homeostasis in AMD pathogenesis.In this study we presented the data suggesting that variants of the


Several studies have been conducted in recent years to evaluate the risk of type 2 diabetes mellitus (T2DM) and polymorphisms of interleukin (IL)-10. However, the results remain conflicting rather than conclusive. This meta-analysis aimed to summarize the current evidence from case-control studies that evaluated this association.We carried out a search in Medline, EMBASE, and the Chinese National Knowledge Infrastructure (CNKI) database for relevant studies. Data were extracted using a standardized form and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association.vs. AA: OR = 1.21, 95% CI = 1.03–1.14; GA/GG vs. AA: OR = 1.22, 95% CI = 1.05–1.41), whereas there was no association between IL-10 −592C/A  or -819C/T  polymorphism and T2DM risk was found in our study.10 studies were included in our meta-analysis and systemic review. Our meta-analysis indicated that IL-10 −1082A/G polymorphism was associated with the risk of T2DM (GA This meta-analysis provides strong evidence that IL-10 −1082A/G polymorphism associated with risk of T2DM. However, no association of the IL-10 −592C/A or −819C/T polymorphism with T2DM risk was found. Additional well-designed large studies were required for the validation of our results. Type 2 diabetes mellitus (T2DM) is one of the main chronic diseases and its complications have become a major cause of morbidity, mortality, and disability in the World. It has been estimated that the number of people with type 2 diabetes will double to at least 350 million worldwide by 2030 unless appropriate action is taken Exel and colleagues discovered that low IL-10 production capacity is associated with the metabolic syndrome and T2DM We carried out a search in Medline, EMBASE, and Chinese National Knowledge Infrastructure (CNKI), covering all papers published up to Aug 2012, using the search terms: (“Interleukin-10” OR “IL-10”) AND (“gene” OR “polymorphism” OR “genetic variant”) AND (“type 2 diabetes mellitus” OR “T2DM” OR “diabetes mellitus” OR “type 2 diabetes”). All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. Only published studies with full-text articles were included.The inclusion criteria were as follows: (a) published in English or in Chinese; (b) used a case-control design; (c) supplied the available genotype frequencies in cases and controls; and (d) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI). Major reasons for exclusion of studies were (a) no control group; (b) duplicate of previous publication.Two investigators reviewed the articles independently to exclude irrelevant and overlapping studies. The results were compared, and disagreements were resolved by discussion and consensus. From each study, the following information was extracted: first author’s surname, year of publication, ethnic descent of the study population , definition of case, age, characteristics of controls, numbers of eligible cases and controls, and genotype distributions in cases and controls.P<0.05 was considered significant. Stratified analyses were performed by ethnicity, age and sources of control. The χ2-based Q statistical test was used for the assessment of the between-study heterogeneity, which was considered significant for P<0.1 P values.The Hardy-Weinberg equilibrium (HWE) was utilized to compare the observed genotype frequencies with expected genotype frequencies in controls for all studies. OR and 95% CI were used to assess the strength of association between IL-10 polymorphisms and the risk of T2DM under homozygote comparison, heterozygote comparison, dominant and recessive genetic model comparison. The significance of the combined OR was determined by the Z-test, in which The search initially identified 421 potentially eligible articles. Of these, the first screening excluded 404 citations based on abstracts or titles, leaving 17 articles for full-text review. The excluded 7 articles had no relative outcomes, no control group, and duplicate of previous publication. We finally included 10 studies in our systematic review and meta-analysis The characteristics of 10 included studies are summarized in vs. AA: OR = 1.07, 95% CI = 0.59–1.93; vs. AA: OR = 0.58, 95% CI = 0.41–0.82),The evaluation of association between IL-10 polymorphisms and T2DM risk was presented in vs. TT: OR = 0.93, 95% CI = 0.49–1.75; vs. TT: OR = 0.63, 95% CI = 0.41–0.95), while these association were not found in European descendents or Asian descendents in the four tested models.There was no statistically significant differences between IL-10 −819C/T polymorphism and T2DM risk  and dominant genetic model . However, no significant association was found in European descendents or African descendents in all tested models.Significant association between IL-10 −1082A/G polymorphism and risk of T2DM was observed under heterozygote comparison , but not sample size , was found to contribute to substantial heterogeneity. However, neither ethnicity  nor sample size was found to contribute to substantial heterogeneity for −1082A/G.There was significant heterogeneity in our meta-analysis. We then assessed the source of heterogeneity for homozygote comparison by ethnicity and sample size. As a result, for −592C/A and −819C/T, ethnicity . However, sensitivity analysis indicated the studies by Kung et al. and Kolla et al. were the main origin of heterogeneity for −1082A/G. The heterogeneity significantly decreased when excluding the two studies (Pheterogeneity = 0.13), while the value of pooled OR was not significantly altered without the two studies .Although the distribution of genotypes in the controls in some studies did not follow HWE, the corresponding pooled OR and between-study heterogeneity were not significant altered without these studies , 4 studies on IL-10 −819C/T polymorphism , and 6 studies on IL-10 −1082A/G polymorphism . To the best of our knowledge, this is the first comprehensive meta-analysis to date investigating the association between IL-10 −819C/T and −1082A/G polymorphisms and T2DM risk. In addition, more studies were included in our study than a recently published meta-analysis concerning −592C/polymorphisms and T2DM risk The findings from our study indicated that IL-10 −1082A/G polymorphism associated with risk of T2DM. However, no association of the IL-10 −592C/A or −819C/T polymorphism with T2DM risk was found. There was evidence of heterogeneity between studies in our analyses. We then assessed the source of heterogeneity for homozygote comparison by ethnicity and sample size. As a result, ethnicity was found to contribute to heterogeneity for IL-10 −592C/A and −819C/T polymorphisms. However, the reasons for heterogeneity in the analysis of −1082A/G were unclear. It may be due to other factors, including the selection of methods, definition of cases, and sample sizes Allele frequency might reflect the natural selection pressures or a balance by other related functional genetic variants and environmental exposures There are some limitations of this meta-analysis should be acknowledged. Firstly, detailed information, such as environmental exposures and gene-gene interactions, were unavailable in most studies, which limited our further assessment of those confounding factors at the patient level, and were incorporated into the analysis. Secondly, some studies with small sample size appear to overestimate the true association due to lack of sufficient power to detect such an association. Thirdly, only English and Chinese language studies were included in this meta-analysis might have led to bias.Even though, our meta-analysis has some advantages. Firstly, the search and selection studies were conducted very strictly, which significantly increased statistic power of this meta-analysis. Secondly, all the studies included in this meta-analysis were case-control researches and contained available genotype frequency, which met our including criterion well. Third, controls in all the included studies were healthy population, which avoided occurring population stratification bias.In conclusion, our meta-analysis suggested that IL-10 −592C/A or −819C/T polymorphism had no association with T2DM risk in all examined patients, whereas there was an association between IL-10 −1082A/G polymorphism and risk of T2DM. However, additional large studies are warranted to validate our findings. Future studies should include multi-ethnic groups and use standardized unbiased genotyping methods, different grades of asthma patients, and well-matched controls.


KIF6 Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the KIF6 Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using KIF6 Trp719Arg as an example.Case-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival . A case in point is the KIF6 Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between KIF6 genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD.Ten replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among KIF6 719Arg variant, should also attenuate the KIF6 719Arg odds ratio in case-control studies.In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the KIF6 Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of KIF6 719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.These computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for  Case-control comparisons are more commonly employed for assessing gene associations than prospective cohort studies ,2. TheirSelection bias refers to subject composition affecting genotype-phenotype associations. For example, non-representative sample of the target population can affect the generalizability of genetic association studies, even if the biases do not differ between genotypes. More importantly with respect to genetic studies are sampling biases that distort genotype-phenotype associations. Such distortions may be less likely to occur in prospective cohort studies than case-control studies .The potential for selection bias is an important limitation of cross-sectional case-control comparisons. Prospective studies  can avoid selection biases, including selection bias due to case fatalities, which can be substantial. For example, the American Heart Association reported that approximately 34% of those who experience a coronary attack in a given year die from it, as do 15% of those experiencing myocardial infarctions [KIF6) Trp719Arg polymorphism (rs20455). Table KIF6 Trp719Arg polymorphism in relation to CHD, including four in the absence of statin use: 1) the nested case-control comparison of placebo-treated West of Scotland Coronary Prevention Study (WOSCOPS) patients [KIF6 719Arg increased primary and secondary CHD risk by about 50% in statin-untreated subjects with moderate to high LDL-cholesterol. This risk estimate is somewhat greater than the 28% increased risk for fatal and nonfatal cardiovascular events for KIF6 719Arg carriers  in PROSPER [KIF6 719Arg carriers [KIF6 719Arg carriers [A case in point is the kinesin-like protein 6  carriers , and thrcarriers -14. Thescarriers , the Carcarriers , and thecarriers ,14. Nevecarriers ,12 or hocarriers ,14.Recently, Assimes et al. reported that KIF6 719Arg carriers showed no greater odds for coronary artery disease when 17,000 cases were compared to 39,369 controls of European descent in a meta-analysis of 19 case-control studies . The stuKIF6 719Arg variant, which suggests poorer survival for this genotype [KIF6 Trp719Arg polymorphism due to its having shown strong, repeated associations with CHD prospectively [This report presents computer simulations to assess the impact of survival bias and effect measure modification by statin use on the detection of genotype-phenotype association in case-control studies. There is a 50% greater risk for recurrent myocardial infarction in carriers of the ectively ,11-14, hKIF6 719Arg carriers are more likely to have a myocardial infarction than is a noncarrier, given that a myocardial infarction has occurred, a KIF6 719Arg carrier is no more likely to die from the event than is a noncarrier. In the absence of any difference in percent fatalities between genotypes, odds ratios of 1.55 (for 50% increased risk for the KIF6 719Arg carriers) and 1.29 (for 25% increased risk for carriers) were obtained regardless of the portion that survived, otherwise the odds ratios were increasingly attenuated as the disparity in fatality rates between genotypes increased. For example, assuming a 25% increased risk for KIF6 719Agr carriers vs. noncarriers and an overall fatality rate of 41.5%, the odds ratio was reduced to 1.18, 1.11, and 1.08, respectively, for 10%, 20%, and 25% differences in %fatality between carriers and noncarriers. The attenuation increases substantially with the fatality rate when the rate was disproportionate between genotypes  in nA second important result of Figure Whereas Figure In prospective cohort studies, genetic variants are identically recruited at baseline and ascertained for incident diseases during follow-up using standardized diagnoses. In case-control studies, spurious associations between genotype and phenotype may arise when the study design or subject participation leads to genotypic differences between cases and controls that are unrelated to the etiology of the disease itself. Responder bias is potentially greater for case-control than cohort studies because recruitment or response may differ between cases and controls. For example, it is not uncommon for control subjects to be derived from geographical, occupational, or environmental sources that differ from those for cases . Cases mKIF6 719Arg carrier are not known to associate with either sex or age, however, CHD is strongly age and sex dependent and the analyses does rely on the adequacy of the statistical adjustment to correct for their effect.In their review of psychiatric case-control studies, Lee et al. concluded, "Genetic studies achieved the poorest ratings in reducing selection bias" . They poOur computer simulations show that survival bias, a type of incidence-prevalence bias , can subKIF6 genotypes and CHD in case-control studies. Four studies have thus far demonstrated that statins significantly reduce CHD-risk in carriers of KIF6 719Arg, whereas noncarriers derive less benefit from statins [KIF6 719Arg in studies that fail to exclude statin users. For example, Figure KIF6 719Arg and CHD in several studies included in the analyses by Assimes et al. [KIF6 719Arg allele distribution between angiographically defined coronary artery disease cases and community controls, which could be due, in part, by high statin use (89%) among the cases, in addition to survival selection. From the descriptions provided, the portion of the statin users that were on their medication prior to their myocardial infarction or angiographically defined coronary artery disease cannot be determined for Ottawa Heart Genomics Studies and the various studies used by Assimes et al. The statin usages cited above would include more aggressive lipid interventions subsequent to the event, and post-incident statin use may actually prevent the loss of KIF6 719Arg carriers among cases.In addition to survival bias, failure to account for statin use may contribute to the weaker association between  statins ,10. Thiss et al.  might bes et al. , 66% in s et al. , 62% in s et al. , 35% in s et al. ) in addis et al.  also fouKIF6 genotypes on CHD that is independent of the extent of atherosclerosis [KIF6 719Arg carriers appear to occur too soon to be attributable to reduced stenosis and may relate to improved plaque stability [KIF6 719Arg carriers [The nonsignificance of the Ottawa Heart Genomics Study may also reflect in part an effect of the clerosis . CHD ristability . Two stutability ,10. In tcarriers ,25.KIF6 719Arg's true risk. The ARIC study showed that homozygotes and heterozygotes of the KIF6 719Arg risk allele had 22% and 12% greater risk for incident CHD, respectively, when adjusted for age and sex [KIF6 719Arg increased the risk of incident myocardial infarction by 29% [KIF6 719Arg had 34% greater risk for myocardial infarction and 24% greater risk for total cardiovascular events  than noncarriers [The potential effect-measure modification due to statin use is not limited to case-control studies. Three of the prospective studies of Table  and sex  's association with CHD. Those having the 677C_T  substitution in the MTHFR gene have lower MTHFR and higher plasma homocysteine levels [MTHFR predicts CHD in the Middle East and Asia where folate intake is low, but not in Europe, North America, or Australia where folate intake is high [The attenuating effects of statin on e levels -29. Where levels -34, othee levels , which h is high . A cauti is high .KIF6 719Arg carriers. Although disproportionate CHD survival for KIF6 Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction, we currently do not have direct evidence for a difference in fatality following cardiovascular events between 719Arg carriers and noncarriers, nor are we aware of other genetic variants that are associated with increased fatality after cardiovascular event. The moderate effect of the KIF6 719Arg variant on the risk of cardiovascular events may suggest that differences in fatality following cardiovascular events are small. This could explain a lack of significant deviation from Hardy-Weinberg equilibrium expectation for the KIF6 Trp719Arg polymorphism in individuals 65 years or older [Our simulated results should be interpreted with caution. The parameters we set in our simulations to illustrate the potential impact of differential fatality and statin use on the outcome of a case-control genetic association study may be less extreme in different settings, for example there may be a smaller attenuating effect of statin on CVD risk in or older , althougKIF6 719Arg carriers is simply a chance occurrence . The Canadian population was chosen to address the potential affects of survival bias for a particular Canadian-based report that failed to demonstrate statistical significance [Simulations were performed using the uniform random number generator and logistic regression statistical analysis of JMP version 5.1 . To assess the impact of survival bias, ten replicates of 1,000,000 observations each were generated based on the age and sex distribution of Canadians from the 2006 census . These w reports ,11-13 an reports ) relativificance . With 95KIF6 719Arg carrier status, ten replicates of 1,000,000 observations were again generated based on the age and sex distribution of Canadians, assigned CVD risk using the Framingham Health Study [KIF6 719Arg carriers. Statin users were chosen at random for 0%, 10%, 20%, ... 90% of the sample. The simulated data were again analyzed by logistic regression analyses with CVD as the dependent variable, and age, sex, and KIF6 719Arg carrier status as the independent variables. We also included statin use as an independent variable to assess whether traditional statistical adjustment corrects for statin use.To assess the bias due to the differential effect of statin treatment by th Study , and 59%KIF6: kinesin-like protein 6; LDL: Low-density lipoproteins; MTHFR: 5,10-Methylenetetrahydrofolate; PROSPER: Prospective Study of Pravastatin in the Elderly at Risk Study; WHS: Women's Health Study; WOSCOPS: West of Scotland Coronary Prevention Study; WTCCC: Wellcome Trust Case Control ConsortiumARIC: Atherosclerosis Risk in Communities study; CARE: Cholesterol and Recurrent Events secondary prevention trial; CHD: coronary heart disease; CHS: Cardiovascular Health Study; CVD: cardiovascular disease; HPS: Heart Protection Study; HRS and PW have received funds from Celera, whose product could profit from this publication. LP has no financial competing interest to report. Celera paid for the preparation and processing charge for the manuscript.PW performed the computer simulations and wrote portions of the paper; LP and RS wrote and revised portions of the paper and provided clinical perspectives to the results.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/12/42/prepub


Recently, there have been a number of studies on the association between cyclin D1 G870A polymorphism and nasopharyngeal carcinoma risk. However, the results of previous reports remain controversial and ambiguous. Thus, we performed a meta-analysis to explore more precisely the association between cyclin D1 G870A polymorphism and the risk of nasopharyngeal carcinoma. No significant association was found between cyclin D1 G870A polymorphism and nasopharyngeal carcinoma risk in total population analysis. In the subgroup meta-analysis by ethnicity, a negative association was shown in Caucasian subgroup, and no significant association in any genetic models among Asians was observed. In summary, positive results have been shown on the search for polymorphic variants influencing the risk of NPC. This meta-analysis provides evidence of the association between CCND1 G870A polymorphism and NPC risk, supporting the hypothesis that CCND1 870A allele probably acts as an important NPC protective factor in Caucasians but not in Asians. Since the results of our meta-analysis are preliminary and may be biased by the relatively small number of subjects, they still need to be validated by well-designed studies using larger samples in the future. Nasopharyngeal carcinoma (NPC) is a malignant epithelial cancer with a strikingly geographic and ethnic distribution. The incidence of NPC is higher in Southeast Asia and Africa, but lower among Caucasians in North America and Europe. Epidemiological studies and experimental researches have implicated genetic susceptibility, Epstein-Barr viral (EBV) infection, and environmental factors in the specific and multifactorial etiology of NPC . In spitCCND1 gene, plays a critical role in the transition from G1 to S phase of the cell cycle during cell division. CCND1 amplification and protein overexpression were detected (described) in NPC patients [CCND1 G870A (rs603965) polymorphism is common in a variety of human tumors, including breast cancer, lung cancer, gastric cancer, gynecological cancer, blood-related cancer, and colorectal cancer (NPC) [CCND1 G870A polymorphism is a silent mutation (Pro241Pro), 870A allele results in an alternatively spliced transcript of CCND1 (transcript b), which has been shown to have a longer half-life than the G allele (transcript a) encoded protein. It suggests that CCND1 870A allele is more likely to contribute to cancer development through promoting the transition between G1 and S phases [CCND1 G870A polymorphism to the increased NPC risk, the results remain controversial.Cyclin D1, encoded by patients . The actpatients , local tpatients . CCND1 Ger (NPC) , 5. Alth G870A rs03965 polConsidering a single study may be insufficient to identify the effect of CCND1 G870A polymorphism on NPC, and the published results have been controversial. We therefore performed a meta-analysis to assess the association between CCND1 G870A polymorphism and NPC susceptibility.We searched the literature databases including PubMed, ISI Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Google Scholar . The search strategy for identifying all possible studies involved usage of the following keywords: “cyclin D1 or CCND1” and “polymorphism or variant or genotype or SNP” and “nasopharyngeal carcinoma or nasopharyngeal cancer or squamous cell cancer of the head and neck or head and neck cancer”. All related studies without language limitation were included. The reference lists of the additional articles reporting the association between CCND1 G870A polymorphism and NPC were hand searched.P value were provided. The major exclusion criteria were (1) duplicate data, (2) case-only studies, (3) review articles, and (4) studies with association between cyclin D1 G870A polymorphism and head and neck cancer, which just described the number and anatomical distribution of tumors without specifically showing the genotype distribution information of each tumor, including NPC.All the studies included in the meta-analysis met the following inclusion criteria: (1) original papers associated cyclin D1 G870A polymorphism with NPC; (2) case control or cohort design was used, and (3) genotype distribution information, odds ratio (OR) with its 95% confidence interval (CIs), and P value for Hardy-Weinberg equilibrium (HWE) test in controls.Data extraction for compliance with the inclusion/exclusion criteria was performed independently by two reviewers. Disagreements were resolved by further discussion among all authors. For each included study, the following information was extracted according to a fixed protocol: (1) name of the first author; (2) year of publication; (3) country; (4) ethnicity; (5) genotyping method; (6) genotype distribution in cases and controls; (7) Z test. Cochran's chi-square-based Q statistic test was performed to evaluate the possible heterogeneity among individual studies. Pooled ORs were calculated according to a fixed model (DerSimonian-Laird method) or a random model (Mantel-Haenszel method) in the absence (P > 0.10) or presence (P ≤ 0.10) of heterogeneity. Heterogeneity was explored using the subgroup analysis of ethnicity (Asians and Caucasians). Publication bias was assessed statistically by Egger's test and Begger's test. The Hardy-Weinberg equilibrium (HWE) was determined using the chi-square test in control groups. All the data analyses were performed using STATA software version 11.0 . All P values were calculated with two-sided analysis, and a P value less than 0.05 was considered as statistical significance.The association between cyclin D1 G870A polymorphism and NPC was estimated by calculating pooled odds ratio (OR) and 95% confidence interval (CI) under a homozygote comparison model (AA versus GG), a heterozygote comparison model (GA versus GG), and a dominant model (AA + GA versus GG), respectively. The significance of pooled OR was determined by As shown in P > 0.05) in all studies except for three studies .Characteristics of the studies included in this meta-analysis were presented in o et al. , P = 0.0h et al. , P = 0.0o et al. , P = 0.0P = 0.969; OR = 0.976, 95% CI = 0.368–2.592 for homozygote comparison model AA versus GG, P = 0.961; OR = 0.811, 95% CI = 0.460–1.429 for heterozygote comparison model GA versus GG, P = 0.469; OR = 0.856, 95% CI = 0.430–1.707 for dominant model GA + AA versus GG, P = 0.660) . In contrast, no such significant association in any genetic models was observed in Asians .The results on the association between cyclin D1 G870A polymorphism and NPC risk and the heterogeneity test were shown in P = 0.000, I2 = 90.5%; homozygote comparison model AA versus GG: P = 0.000, I2 = 90.2%; heterozygote comparison model GA versus GG: P = 0.001, I2 = 77.6%; dominant model GA + AA versus GG: P = 0.000, I2 = 86.6%)   and emplP = 0.143; dominant model GA + AA versus GG: P = 0.082), but indicated evidence for publication bias for the other two genetic models . Beggar's rank correlation showed no evidence for publication bias for three of the four genetic models  but indicated publication bias for the homozygote comparison model AA versus GG (P = 0.027)  .CCND1 gene encodes a key cell cycle regulatory protein, cyclin D1, which regulates transition from G1 to S phase during cell division. Cyclin D1 has been recognized as a promising biomarker for predicting tumor behavior [Cell cycle regulation plays an important role in the development of cancer by influencing cell proliferation, differentiation, and apoptosis . The CCNbehavior . In recebehavior , laryngebehavior , breast behavior , colorecbehavior , 28, andbehavior . But sevbehavior  and colobehavior  or was nbehavior –36. SincCCND1 G870A seemed to be a protective factor for NPC in Taiwan of China [Deng et al. found that cyclin D1 G870A polymorphism was associated with the susceptibility to NPC, because the GG and AG genotypes in NPC patients were significantly higher than those in normal controls . But Shiof China . Catarinof China . TherefoIn the subgroup meta-analysis based on ethnicity, compared with G allele, a significantly decreased risk of NPC was associated with A allele; compared with GG genotype, a significantly decreased risk of NPC was associated with AA genotype, GA genotype, and combined AA/GA genotype in the Caucasian subgroup. Further investigations on a larger scale on Caucasian population may be needed to confirm this result. In the Asian subgroup, no significant association was found in the different genetic models. Our results indicate that ethnicity may be a critical factor affecting effects of the polymorphic alleles on susceptibility to NPC.Despite these advantages, some limitations in the current meta-analysis should be considered with caution. Firstly, the controls were not uniformly defined. Although most control groups were selected from healthy populations, some might have a benign disease. Therefore, there is a lack of proper matching, and the results are based on unadjusted estimates. Secondly, the analysis did not consider gene-gene and gene-environment interactions due to the lack of sufficient data. Thirdly, environmental and lifestyle-related factors may influence the results of this analysis. A more precise analysis with individual data available might be considered, which could allow an adjustment estimate by sex, age, body weight, and lifestyle such as smoking and alcohol drinking. Fourthly, there is evidence of publication bias in the formal evaluation used in this study. The results of our meta-analysis may be biased by the relatively small number of subjects. Therefore, our conclusion still needs to be validated by well-designed studies with larger sample size in the future. Finally, and most importantly, whether the CCND1 G870A polymorphism is independently predictive of cancer risk remains controversial.In summary, positive results have been shown in the search for polymorphic variants influencing the risk of NPC. This meta-analysis provides evidence of the association between CCND1 G870A polymorphism and NPC risk, supporting the hypothesis that CCND1 870A allele probably acts as an important NPC protective factor in Caucasians, but not in Asians.