PNPLA3) predisposes susceptibility to NAFLD; however, its association with steatosis grade is inconsistent in the literature. In particular, there was no significant association found between I148M and steatosis grade in two East Asian-based studies. In this study we aim to investigate whether I148M is associated with the ultrasonography-determined steatosis degree in Chinese adults.Nonalcoholic fatty liver disease (NAFLD) is an escalating medical problem worldwide. A nonsynonymous single nucleotide polymorphism rs738409 (I148M) in patatin-like phospholipase domain-containing protein 3 . We also confirmed the interaction between I148M variation and body mass index towards elevated plasma alanine aminotransferase levels in cases .The I148M variant was associated with the ultrasonography-determined steatosis degree with the M allele frequencies being 0.32, 0.54, and 0.87 in mild (n=105), moderate (n=83), and severe (n=15) cases, respectively (PNPLA3 I148M variant is associated with the ultrasonography-determined steatosis degree in Chinese population.The  Nonalcoholic fatty liver disease (NAFLD) is an escalating medical problem worldwide. It affects 20-34% of the population in Western countries ; althougPNPLA3) that substitutes methionine for isoleucine at residue 148 (I148M) was first reported to be associated with hepatic triglyceride content in a genome-wide screen [NAFLD is a multifactorial disorder associated with obesity, insulin resistance, type 2 diabetes, and dyslipidemia ,7. Famile screen ; subseque screen -19. The e screen ); howevee screen ,16. In pPNPLA3 I148M variant is not associated with body-mass-index (BMI) in the general population [Although the pulation ,13, it wpulation  and chilpulation ,23. Furtpulation . More repulation . In thisA total of 203 unrelated adults with NAFLD were recruited from an outpatient liver clinic at the First Affiliated Hospital of China Medical University in Shenyang, China, between October 2010 and April 2011. The patients were confirmed to have hepatic steatosis by liver ultrasonography and classified into three categories—mild, moderate, and severe—according to established criteria . In partχ2 goodness-of-fit test in cases and controls, respectively.Age and sex were self-reported. BMI was calculated according to the measured height and weight at the time of recruitment. Venous blood samples were obtained from the subjects after an overnight fast (12 hours). Plasma ALT, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), fasting blood glucose (FBG), triglycerides, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) levels were measured using an automated analyzer. Genomic DNA was extracted from leukocytes using AxyPrep Whole Blood Genomic DNA Miniprep Kit . The I148M variant was genotyped using a TaqMan assay on a 7900HT Fast Real-Time PCR instrument  at 50°C for 2 min, 95°C for 10 min, and then 40 cycles of 95°C for 15 sec and 60°C for 1.5 min. Hardy-Weinberg equilibrium (HWE) was examined by Pearson’s t-test for continuous variables and by a proportion test for categorical variables. Comparisons between caterogies of cases were performed by analysis of variance. Linear regression models were fit to test association between genotype and continuous phenotypes, and logistic regression models were fit to test association between genotype and categorical phenotype. Bonferroni correction was performed to correct for multiple testing. The genotypic value was coded in an additive manner, i.e., 0, 1, and 2 denoted II, IM, and MM genotypes, respectively. The interaction between I148M and BMI for a continuous trait—ALT—was tested by examining the interaction term in a linear regression model; the interaction for an ordinal trait—the ultrasonography-determined steatosis degree—was tested by examining the interaction term in an ordered logistic regression model; the interaction for a binary trait—NAFLD—was tested either by examining the interaction term in a logistic regression model using both cases and controls, or by examining the association between I148M and BMI using only cases. We estimated the power to detect interaction a priori given the sample size; when there was no significant interaction detected, we also estimated sample sizes required to achieve the power of 0.8. The power analyses were performed for a quantitative trait [Comparisons of demographic and clinical features between cases and controls were performed by a two-sample ve trait  and for ve trait ,29 and cve trait  designs.ve trait  except tve trait ,29.P < 0.01). Liver enzyme levels ALT and AST increased with the steatosis degree  whereas GGT levels did not (P > 0.10). Triglycerides levels showed a marginal increase with the increase of the steatosis degree , whereas LDL-C and HDL-C levels did not . FBG levels were higher in the 15 severe cases, though not statistically significant .The comparisons of demographic, clinical, and genetic characteristics between the 203 NAFLD cases and 202 controls were reported elsewhere . Here weP-value=0.59), which guaranteed the genotyping quality, but in cases it was out of HWE , which indicated its association with the disease status [P-value=1.5×10-4) [P–value = 7.6×10-8). We further investigated the association between I148M and other clinical parameters in cases and controls, respectively , and AST showed a tendency of increase but not statistically significant , whereas LDL-C levels showed a tendency of decrease . None of the clinical features were significantly associated with I148M in controls.The distribution of the I148M variant in cases and controls was summarized in Table e status . We prev.5×10-4) . This vaP-values > 0.10). Therefore we investigated their interaction towards ALT levels and NAFLD susceptibility assuming independence between them. Given the allele frequency of I148M variant in cases and the distributions of ALT levels and BMI in each genotypic category, the power to detect a significant interaction between I148M and BMI at the level of 0.05 was greater than 0.99 [P–value = 4.4×10-4) by a linear regression model. Stratifying the cases into quarters by BMI, it showed the MM genotype interacted with high BMI to elevate ALT levels . To detect a significant interaction at the level of 0.05 with a power of 0.8, it would need a sample size of either 2,362 cases or 1,316 cases and 1,316 controls. There was no significant interaction between I148M and BMI towards elevated AST levels or the ultrasonography-determined steatosis degree .There was no statistically significant association between I148M and BMI in either cases or controls, or the combined sample ; when the ALT levels were adjusted for, the association became more significant . This result was consistent with that in another large study [In silico bioinformatic analysis suggested that PNPLA3 be involvoed in the metabolism of apoB-containing lipoproteins [in vitro experiments suggested that PNPLA3 be involved in triglycerides metabolism [P–value > 0.10). However, there were reports on their association in obese populations [Although the association of ge study , implyinproteins . Althougtabolism ,42, thertabolism  or in ouulations ,41. We sPNPLA3 I148M variant. There was no significant association between I148M and BMI in either cases or controls, consistent with the results in general populations [It is intriguing to investigate whether metabolic comorbidities such as obesity and insulin resistance, which are associated with the pathogenesis of NAFLD, are also influenced by the ulations ,13. It wulations . There wulations ,24 and tulations . In thisThe authors declare no competing interest.YL and ZT carried out clinical studies; CX and HK carried out data analysis; YL and CX were in charge of manuscript writing and project supervising. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/13/113/prepub


Epidemiological studies have evaluated the association between tumor necrosis factor α (TNF-α) single nucleotide polymorphisms (SNPs) and duodenal ulcer (DU), but the results remain inconclusive. The aim of this study was to perform a meta-analysis to investigate a more authentic association between TNF-α SNPs and DU.We performed the meta-analysis by searching PubMed, Embase, and Web of Science databases from the first available year to Sep. 5, 2012. Additionally, checking reference lists from identified articles, reviews, and the abstracts presented at related scientific societies meetings were also performed. All case-control studies investigating the association between TNF-α SNPs and DU risk were included. The association was assessed by odds ratio (OR) with 95% confidence interval (CI). Publication bias was analyzed by Begg's funnel plot and Egger's regression test.A total of sixteen studies reporting TNF-α −308G/A, −1031T/C, −863C/A, −857C/T, and −238G/A polymorphism were included in our final meta-analysis. There was no statistically significant association between −308G/A polymorphism and DU in the overall study population, as well as subgroup analyses by ethnicity, study design, and H. pylori status. As for −1031T/C, −863C/A, −857C/T, and −238G/A, results of our meta-analyses showed no statistical evidence of significant association. Power calculation on the combined sample size showed that the statistical powers were all lower than 80% for all the meta-analyses.The data suggests that there is no statistical evidence of significant association between the studied TNF-α SNPs and DU. However, this conclusion should be interpreted with caution as low statistical powers were revealed by power calculations. In future, larger sample-size studies with homogeneous DU patients and well-matched controls are required. Duodenal ulcer (DU) is one type of peptic ulcer that occurs in the duodenum. DU may result from infection of Helicobacter pylori (H. pylori) bacteria, overuse of alcohol, and medications such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) With respect to host genetic factors, our previous studies demonstrated no association between DU and interleukin (IL)-1 β 511 C/T and 31 C/T polymorphisms, but significant association between IL-8 −251 T/A polymorphism and DU This meta-analysis followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines The inclusion criteria were as follows: (1) studies on the relationship between TNF-α gene polymorphisms and DU, including −308G/A, −1031T/C, −863C/A, −857C/T, −238G/A, −376 G/A, and −806 C/T; (2) published case-control studies; (3) studies with full text articles; (4) sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI).P<0.05 of HWE was considered significant), respectively. Different ethnicities were categorized as Caucasian, Asian, African, American Indian, and mixed. Study design was stratified to population-based (PB) studies and hospital-based (HB) studies. Total numbers of cases and controls, and frequency of −308G/A, −1031T/C, −863C/A, −857C/T, −238G/A, −376 G/A, and −806 C/T mutation in cases and controls regardless of H. pylori status were extracted. When studies reported genotype distributions for H. pylori negative and H. pylori positive only, we also extracted data of each group separately for subgroup analyses.The information was carefully extracted by the same two authors (Zhang BB and Yin YW) according to the inclusion criteria listed above independently. Disagreement was resolved by consensus. If these two authors could not reach a consensus, another author (Sun QQ) was consulted. The following data were collected from each study: first author's name, publication date, country, ethnicity, study design (source of controls), and evidence of Hardy-Weinberg equilibrium (HWE) (Two authors (Zhang BB and Yin YW) of this article independently assessed the qualities of included studies using the Newcastle-Ottawa Scale (NOS) 2 statistic, P<0.10 and I2>50% indicated evidence of heterogeneity P<0.05 was considered representative of statistically significant publication bias) http://hydra.usc.edu/gxe/) Combined ORs with their 95% CIs were calculated respectively for four genetic models: allelic model , additive model (2/2 vs. 1/1), dominant model (1/2+2/2 vs. 1/1), and recessive model (2/2 vs. 1/2+1/1), in which 2 indicates the minor allele Table S1 and The present study met the PRISMA statement requirements (S4). Power calculation on the pooled frequencies showed that the statistical powers were all lower than 80% for all the above meta-analyses . However, statistical evidence of publication bias were found using Egger's regression test for allelic model of −238G/A mutation and recessive model of −857C/T mutation. The results were as follows: for −308G/A mutation ; for −238G/A mutation ; for −1031T/C mutation ; for −863C/A mutation ; for −857C/T mutation .The shapes of the funnel plots did not reveal any evidence of obvious asymmetry visually  demonstrated that all the meta-analyses were underpowered. Even with over 1,800 cases and over 3,000 controls, the power was very low. It indicated that the combined sample sizes in our study were still inadequate to detect the association between TNF-α gene SNPs and DU. In addition, gene-gene interactions should be considered. For further study, gene to gene interactions with the generalized multifactor dimensionality reduction method, which has been applied widely There are some limitations of this meta-analysis. Firstly, the linkage disequilibrium was found among the SNPs analyzed. Haplotype analysis may provide more information in evaluating the association between TNF-α SNPs and DU risk. Secondly, some inevitable bias may exist in the results as our meta-analysis only focused on papers published in English language and studies with full text articles, missing some eligible studies which were unpublished or reported in other languages. Thirdly, there was considerable heterogeneity among the included studies. Heterogeneity may affect the precision of results, despite the use of appropriate meta-analytic techniques with random-effects model.Nonetheless, to the best of our knowledge, this is the first meta-analysis focusing on the relationship between TNF-α SNPs and DU risk. Our meta-analysis suggests that there is no statistical evidence of significant association between TNF-α SNPs and DU. However, this conclusion should be interpreted with caution as low statistical powers were revealed by power calculations. In future, larger sample-size studies with homogeneous DU patients and well-matched controls are required.Figure S1Forest plots of all models for −238G/A(TIF)Click here for additional data file.Figure S2Forest plots of all models for −857C/T(TIF)Click here for additional data file.Figure S3Forest plots of all models for −863C/A(TIF)Click here for additional data file.Figure S4Forest plots of all models for −1031T/C(TIF)Click here for additional data file.Figure S5Funnel plots of all models for −308G/A(TIF)Click here for additional data file.Figure S6Funnel plots of all models for −238G/A(TIF)Click here for additional data file.Figure S7Funnel plots of all models for −857C/T(TIF)Click here for additional data file.Figure S8Funnel plots of all models for −863C/A(TIF)Click here for additional data file.Figure S9Funnel plots of all models for −1031T/C(TIF)Click here for additional data file.Table S1PRISMA 2009 Checklist(DOC)Click here for additional data file.


Unilateral visual neglect is commonly defined as impaired ability to attend to stimuli presented on the side of visual space contralateral to the brain lesion. However, behavioral analyses indicate that different neglect symptoms can dissociate. The neuroanatomy of the syndrome has been hotly debated. Some groups have argued that the syndrome is linked to posterior parietal cortex lesions, while others report damage within regions including the superior temporal gyrus, insula, and basal ganglia. Several recent neuroimaging studies provide evidence that heterogeneity in the behavioral symptoms of neglect can be matched by variations in the brain lesions, and that some of the discrepancies across earlier findings might have resulted from the use of different neuropsychological tests and/or varied measures within the same task for diagnosing neglect. In this paper, we review the evidence for dissociations between both the symptoms and the neural substrates of unilateral visual neglect, drawing on ALE (anatomic likelihood estimation) meta-analyses of lesion-symptom mapping studies. Specifically, we examine dissociations between neglect symptoms associated with impaired control of attention across space (in an egocentric frame of reference) and within objects . Results of ALE meta-analyses indicated that, while egocentric symptoms are associated with damage within perisylvian network  and damage within sub-cortical structures, more posterior lesions including the angular, middle temporal, and middle occipital gyri are associated with allocentric symptoms. Furthermore, there was high concurrence in deficits associated with white matter lesions within long association  and projection  pathways, supporting a disconnection account of the syndrome. Using this evidence we argue that different forms of neglect link to both distinct and common patterns of gray and white matter lesions. The findings are discussed in terms of functional accounts of neglect and theoretical models based on computational studies of both normal and impaired attention functions. The complexity of the visual world requires us to have the ability to select and process behaviorally relevant stimuli while ignoring the rest of the scene. We also need to have the capacity to shift attention between different elements as we search for relevant stimuli. The cognitive processes that underlie these abilities are collectively known as visuospatial attention. These cognitive mechanisms are indispensable for numerous daily activities, as illustrated by the immense problems experienced by individuals suffering from visuospatial deficits after brain damage. The most widely studied disorder of visuospatial attention is unilateral visual neglect  meta-analyses. Specifically, our analyses examined (i) the overall convergence between the results from different lesion-symptom mapping studies concerned specifically with visual neglect , (ii) the concurrence in the damage within white matter pathways associated with neglect symptoms, and (iii) the concurrence in lesion sites associated with deficits in the control of attention either across space (egocentric frame of reference) or within objects , to evaluate whether behavioral dissociations within the neglect syndrome are matched by different lesion patterns. For this last analysis we fractionated data from studies using different assessment tools to measure neglect symptoms. It should be noted that our classification of the differential assessments of neglect depends on inferences about the underlying processes. For example, we assume that tasks such as line cancelation require that multiple stimuli are coded in relation to the patient’s body . In contrast, tasks such as line bisection could reflect either separate coding of the perceived ends of the lines in relation to the patient  or perception of the line as a single object  associated with unilateral visual neglect as well as providing evidence for disconnection accounts of the syndrome. The findings are discussed in terms of functional accounts of neglect and theoretical models based on computational modeling of both normal and impaired attention functions.For the purpose of the current study we conducted a systematic literature search to indentify relevant papers reporting the neuronal substrates of the heterogeneous symptoms associated with unilateral visual neglect. All searches were carried out using PubMedThe inclusion criteria were as follows: 1) studies published in peer-reviewed journals; (2) use of lesion-symptom mapping approaches as defined in the Introduction, i.e., either lesion subtraction methods , VBM, or VLSM/VLBM methods; (3) the studied sample consisted of mainly brain injured patients and both experimental and control patients groups were described/defined clearly; (4) the findings were reported using spatial coordinates in either Montreal Neurological Institute  for each individual study entered into our ALE meta-analyses. In Table Analysis 1 included data from all relevant papers reporting the neural substrates of unilateral visual neglect considering it as a unitary syndrome, not separating out patients according to different types of symptom as well as not differentiating between gray versus white matter lesions associated with the syndrome. Specifically, in Analysis 1 we included all the data from studies examining neglect, diagnosing neglect either from one of the commonly used tests or a battery of measures without applying any prior selection criteria. Analyses 2 and Analysis 3 directly examined the link between the heterogeneity of neglect and any associated neural substrates by fractionating lesion sites associated with deficits in allocating attention either across space  or within objects . The data included in Analysis 2 came from studies that defined neglect exclusively using either target cancelation tests or both target cancelation and figure copying tests, measuring the patient’s ability to attend to stimuli presented on the right and left side of egocentric space  followed by analysis of concurrence in lesion sites associated more specifically with deficits in the control of attention within objects  after excluding reports using line bisection . As recently much attention has been given to white matter lesions and disconnection accounts of the syndrome, Analysis 6 was performed on a subset of data specifically describing the link between neglect symptoms and white matter damage based on data from identified studies diagnosing neglect based on either one of the commonly used tests or on battery of neglect diagnostic measures without applying any selection criteria. Finally, Analyses 7 and Analysis 8 examined the link between white matter lesions and the specific symptoms of neglect associated with the control of attention either in relation the patient’s body  or within objects .In order to examine dissociations between both the symptoms and the neural substrates of neglect, we performed several different ALE meta-analyses . The relevant papers included in these analyses are listed in Table We performed the meta-analyses using BrainMap GingerALE 2.1 softwarep < 0.05 FDR  corrected for multiple comparisons and a minimum cluster size of 200 mm3  meta-analyses using as inputs coordinates describing foci identified in functional neuroimaging studies .Table Analysis 2 we identified 15 studies  and six studies . Ten of the identified studies  reported neglect associated with damage within white matter (not applying any selection criteria with regards to the tests of neglect) and these data were included in Analysis 6  and four studies .For The ALE meta-analysis for the main effect, i.e., the overall concurrence in the reported neural substrates of unilateral visual neglect (not differentiating between either different symptoms or gray versus white matter lesions) revealed 15 significant clusters Table . HoweverAnalysis 2 and Analysis 3 was not as robust as in the case of the white matter analysis reported below but the findings were nevertheless striking. The two most concurrent clusters (contributed respectively by 7 and 5 out of 20 experiments) identified in Analysis 2 (egocentric neglect) were located within the right superior temporal gyrus , right insula , and sub-cortical structures including the right putamen  and thalamus . The two most concurrent clusters  identified in Analysis 3  were located within the right angular gyrus , right temporo-parietal junction , right middle temporal gyrus , and sub-cortically within the right SLF . Strikingly, these two analyses indicated that, while egocentric symptoms were associated with damage within perisylvian network  and damage within sub-cortical structures, more posterior lesions including the angular, middle temporal, and middle occipital gyri were associated with allocentric symptoms  revealed 16 significant clusters associated with egocentric symptoms and 10 clusters associated with allocentric symptoms Table A,B. The Analysis 4) and the neural substrates associated with allocentric symptoms as measured by diagnostic tests excluding line bisection . The ALE meta-analysis on biases in line bisection revealed one significant cluster , revealed six significant clusters  or allocentric space  revealed four significant clusters associated with egocentric symptoms and four clusters with allocentric symptoms , right superior thalamic radiation , and right ILF . The most concurrent cluster  was located within the right SLF , the right IFOF, and the right posterior thalamic radiation . Strikingly, these two analyses  indicated that egocentric and allocentric symptoms were associated with lesions within common long association and projection pathways, in particular the SLF and the thalamic radiation.The ALE meta-analysis examining concurrence in the reported damage within white matter pathways associated with left neglect, not differentiating between the different symptoms of neglect , the consistency across the reported findings was relatively poor, though one of the identified clusters was contributed to by approximately 50% of all experiments. This covered regions within posterior parietal cortex (IPL), the insula, and the thalamus as well as within white matter pathways. Strikingly, when the different tests were not differentiated, there was high overall concurrence in white matter lesions within the long association SLF  and projection  pathways. This provides strong evidence for a disconnection account of the syndrome, which can generate a common pattern of deficit across different tests. While the assessment of common cortical damage across the different tests of neglect generated moderate results, the results were stronger when we separated out tests sensitive to the positions of elements in egocentric and allocentric reference frames. Here our concurrence analyses indicated that egocentric symptoms were associated with damage within the perisylvian network  along with damage within sub-cortical structures, while more posterior lesions including the angular, middle temporal, and middle occipital gyri) were associated with allocentric symptoms.Here, we examined data indicating dissociations between the heterogeneous symptoms and the neural substrates of unilateral visual neglect based on ALE meta-analyses of lesion-symptom mapping studies. There is a substantial body of evidence demonstrating that different neuropsychological tests and/or even varied measures within the same task used for diagnosing neglect can reveal different symptoms of this heterogeneous syndrome whilst also varying in their overall sensitivity for detecting mild to moderate symptoms  that multiple factors arising from variability in the neglect diagnosis explain the discrepancies reported in the literature on the neuronal substrates of unilateral visual neglect. It is plausible that other modulating factors, such as for example the neuroimaging modality used , the data analysis methods  and the time of assessment, i.e., acute versus chronic brain injury, may also be important. However, because of the much higher concurrence demonstrated after fractionating the symptoms of neglect, we believe that the diagnostic tools are adequate to explain the literature discrepancies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


XRCC3) Thr241Met has been implicated to alter the risk of ovarian cancer, but the results are controversial. In order to get a more precise result, a meta-analysis was performed. All eligible studies were identified through an extensive search in PubMed, Excerpta Medica Database (Embase), Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature Database before August 2013. The association between the XRCC3 Thr241Met polymorphism and ovarian cancer risk was conducted by odds ratios (ORs) and 95 % confidence intervals (95 % CIs). Finally, a total of four publications including seven studies with 3,635 cases and 5,473 controls were included in our meta-analysis. Overall, there was no association between XRCC3 Thr241Met polymorphism and risk of ovarian cancer under all five genetic models in overall population . In the subgroup analysis according to ethnicity, the results suggested that XRCC3 Thr241Met polymorphism was not associated with the risk of ovarian cancer in Caucasians population. No significant association was found between the XRCC3 Thr241 Met polymorphism and the risk of ovarian cancer. Given the limited sample size and ethnicities included in the meta-analysis, further large scaled and well-designed studies are needed to confirm our results.Genetic polymorphism of X-ray repair crosscomplementing group 3 ( MTHFR C677T [Ovarian cancer is the eighth most commonly diagnosed cancer and the fifth leading cause of cancer death in the females worldwide with an estimated 225,500 new cases and 140,200 deaths every year , 4. SincXRCC3). XRCC3, located at chromosome 14q32.3, is a member of DNA repair genes and involved in maintaining the stability of genome by homologous recombination repair for DNA double-strand breaks [XRCC3, which substitutes at codon 241 in exon 7, with a C to T transition  [XRCC3 gene “-18067C/T” for short in this meta-analysis. Previous studies were performed to investigate the relationship between the XRCC3-18067C/T polymorphism and ovarian cancer risk [XRCC3-18067C/T polymorphism and ovarian cancer risk more precisely, we conducted a meta-analysis.Another candidate gene that has received a lot of attention is the X-ray repair cross-complementing group 3 . We callcer risk –16. HoweXRCC3-18067C/T polymorphism and ovarian cancer risk, we conducted an extensive search in PubMed, Excerpta Medica Database (Embase), Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature Database before August 2013 by using the terms as follows: “XRCC3” or “X-ray cross complementing group 3” in combination with “polymorphism,” “polymorphisms,” “variant,” or “mutation” in combination with “ovarian cancer,” “ovarian carcinoma,” or “ovarian tumor” for all publications. There was no language limitation. Additional studies were identified by a hand search of the references of original studies. Review articles were also examined to find more eligible studies.To identify all currently available studies on the association between XRCC3-18067C/T polymorphism and ovarian cancer, (b) a case–control design, (c) the genotype distribution among the control population was consistent with Hardy–Weinberg Equilibrium (HWE), and (d) sufficient reported genotypic frequencies in both cases and controls for estimating an odds ratio (OR) with its 95 % confidence interval (95 % CI). The following exclusion criteria were used for excluding studies: (a) control population including patients, (b) studies contained duplicate data, and (c) case reports or reviews.Studies to be included in the meta-analysis were required to meet the following criteria: (a) it assessed the association between the Information was carefully extracted from all eligible publications by two authors independently according to the inclusion criteria listed above, disagreements were resolved through consensus, if could not reached agreement, another author was consulted to resolve the debate. The following information was extracted: the name of first author, year of publication, country of origin, ethnicity of the population, genotyping methods, source of the control group, sample size of cases. Different ethnicities were categorized as Caucasians and mixed.XRCC3-18067C/T polymorphism and ovarian cancer susceptibility was measured by the pooled ORs with corresponding 95 % CIs in five genetic models: allele contrast (T vs. C), homozygote (TT vs. CC), heterozygote (TC vs. CC), recessive (TT vs. TC/ CC), and dominant (TT/TC vs. CC) models, respectively. Heterogeneity was checked by the Chi-square based Q statistic. If the result of the heterogeneity test P < 0.10, suggested the between-study heterogeneity was existed, ORs were pooled by random-effects model (DerSimonian and Laird method) [I2 value [I2value >50 % or P < 0.10), the overall estimate of risk was calculated by the random-effects model; when obvious heterogeneity was absent, the fixed-effects model was used.The possible association between the  method) . Otherwi2 value . If obvihttp://ihg2.helmholtz-muenchen.de/cgibin/hw/hwa1.pl) to confirm whether the genotype distribution of XRCC3-18067C/T in controls agreed with HWE if P > 0.05 suggests the controls followed HWE balance. Egger’s linear regression test was applied to examine the possible publication bias, Egger’s test  [P < 0.05 was considered statistically significant.The HWE was assessed by using a professional web-based program (on bias) . Publicaon bias) . StatistP > 0.05). The study characteristics included in the meta-analysis were listed in Table After carefully selecting based on the search criteria above, a total of four publications including seven studies with 3,635 cases and 5,473 controls were included in our meta-analysis –16, all XRCC3 Thr241Met polymorphism and risk of ovarian cancer under all five genetic models in overall population . In the subgroup analysis according to ethnicity, the results suggested that XRCC3 Thr241Met polymorphism was not associated with the risk of ovarian cancer in Caucasians population  and dominant (TT/TC vs. CC) genetic models in overall population. To examine the source of heterogeneity, we assessed the dominant model (TT/TC vs. CC) by ethnicity. However, the results showed there was no obvious heterogeneity in the subgroup analyses of both Caucasians and mix, suggesting that ethnicity was the major source of heterogeneity in our meta-analysis.P > 0.05, data not shown).Funnel plot and Egger’s test were used to assess the publication bias in this meta-analysis. Funnel plot is relatively straightforward to observe whether the presence of publication bias and Egger’s test was provided statistical evidence of symmetries of the plots. As a result, both the shape of the funnel plot and Egger’s test value did not suggest any evidence of obvious asymmetry (Fig. XRCC3 plays a critical role in maintaining genomic integrity by repairing radiation-induced DNA double-strand breaks, and the XRCC3 polymorphism may affect the DNA repair capacity of its encoded protein, thus, contributes to the development of cancers [It is well known that SNPs are the most common sources of human genetic variation, and they may contribute to an individual’s susceptibility to cancer.  cancers , 12.XRCC3 Thr241Met polymorphism, a growing number of studies suggested that XRCC3 Thr241Met polymorphism plays an important role in the development of cancers, such as glioma [XRCC3 Thr241Met polymorphism in ovarian cancer risk have been performed, but the results are controversial. Different study designs, various methodologies, and different population backgrounds would inevitably increase the risk, which should be responsible for the controversial conclusions. However, meta-analysis is a powerful tool for analyzing cumulative data of studies which the individual sample sizes are small and the statistical power is low. No meta-analysis evaluating on the association between the XRCC3 Thr241Met polymorphisms and ovarian cancer risk has been performed. So, we carried out a meta-analysis.Since the identification of s glioma , hepatocs glioma , head ans glioma , and so XRCC3 Thr241Met polymorphism was not associated with ovarian cancer risk in the overall populations. Subgroup analysis based on ethnicity indicated that XRCC3 Thr241Met polymorphism was not a risk factor for Caucasians, but is a risk for mix. The results about mix may not be accurate because only one study was found about mix; the sample size is too small to explain the conclusion.A total of four publications including seven studies with 3,635 cases and 5,473 controls were included in our meta-analysis –16. The XRCC3 Thr241Met polymorphism and the susceptibility of ovarian cancer that is because different countries may have different genetic backgrounds and environmental exposures. Publication bias is another important factor which may have a negative effect on the meta-analysis. Both Funnel plot and Egger’s test were used to assess the publication bias of our meta-analysis. The shape of funnel plot and statistical results show no obvious publication bias found; this indicates that the publication bias has little effect on the results of our study, and the results of our meta-analysis are relatively stable.The heterogeneity is a very important part of a meta-analysis, and finding the possible sources for the high heterogeneity is very important , 27. TheThere are several limitations in our meta-analysis that should be considered. Firstly, the sample sizes are relatively small; there are only seven studies with a total of 3,635 cases and 5,473 controls included in our meta-analysis. More studies with large sample size and well-designed are needed to further identify this association more comprehensively. Secondly, studies included in the present meta-analysis mainly provided data towards Caucasians in the light of the race-specific association probably exist; other ethnicities including Asians, Africans, and others should be investigated in future studies. Thirdly, subgroup analyses according to age, radiation exposure, histological types, and other elements have not been performed due to insufficient relevant data available in the primary studies. Finally, only published and English studies were included in this study; thus, publication and potential language biases may occur.XRCC3 Thr241Met polymorphism and the risk of ovarian cancer. No significant association was found between the XRCC3 Thr241 Met polymorphism and the risk of ovarian cancer. Given the limited sample size and ethnicities included in the meta-analysis, further larger scaled and well-designed studies are needed to confirm our results.In summary, our meta-analysis systematically analyzed the association between


The purpose of this study is to explore the relationship between the interactions of CYP2C19 gene polymorphisms and several environmental factors and oesophageal squamous cell carcinoma (OSCC).In a case-control study of OSCC patients (n = 350) and healthy controls (n = 350), we investigated the roles of polymorphism in the CYP2C19 gene by the use of polymerase chain reaction - restriction fragment length polymorphism (PCR – RFLP) analysis.*3 AG+AA genotype was significantly more prevalent in OSCC patients . Multiple logistic regression analysis showed drinking  and smoking  was the independent risk factor of OSCC respectively, and there were significant interaction between CYP2C19*3 and drinking .The CYP2C19*3 polymorphism and OSCC were synergistically and significantly associated in Chinese Han patients.The CYP2C19 Oesophageal squamous cell carcinoma (OSCC) is a common cancer among people in China Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs). Current researches suggested that some CYP isoforms, such as CYP1A Recently, a common genetic variant, CYP2C19*3 (G636A) gene was reported in some studies However, the role of this gene variant in OSCC has not been sufficiently investigated. Normally, Asian people had a higher incidence of CYP2C19*3, which was usually about 13–16%, but in Caucasian people it was only 1–3% as well In the present study, we hypothesized that those with the CYP2C19*3 may have a higher risk for OSCC. We also speculated that there should be a synergistic interaction between the effect of several environmental factors and the genetic variation for the OSCC.The present study was approved by the Ethics Committee of the Kunming General Hospital of Chengdu Military Region.All the patients (n = 350) were diagnosed with histologically confirmed OSCC at Kunming General Hospital of Chengdu Military Region. Controls (n = 350) were age, sex, and geographically-matched individuals to the patients but with no obvious sign of disease. Controls with prior history of cancer were excluded. The patients and controls were recruited between 2009 and 2011. And both the patients and the controls are the Chinese Han ethnic origin.Blood samples were collected with a standard venipuncture technique and EDTA-containing tubes. DNA was extracted from peripheral vein blood leukocytes using a whole blood genome extraction kit (Beijing Boiteke Corporation) according to the manufacturer's instructions. Samples were coded to protect donor identity and to allow blinding of the investigators who carried out the genotyping.A standard questionnaire was administered to cases and controls by trained medical doctors to elicit information on demographic variables, including cigarette smoking, drinking history, fruit and vegetable intake, family history of cancer, and prolonged use of wood or charcoal as sources of fuel for cooking and heating . Persons reporting regular tobacco use in the previous 6 months were considered as smoker. Persons who were ingesting alcohol in the last 6 months were considered to be alcohol dinking 5′- CATCCTGGGCTGTGCT-3′; and the reverse primer is 5′- AGGGCTTTGGAGTTTAGTG-3′; annealing temperature is 52°C. The PCR product (15 µL) was incubated with BamH I (Fermentas corporation) 5U in a total volume of 25 µL overnight at 37°C, and the resulting fragments were separated on a 1.5% agarose gel. The presence of the G636A variant creates a BamH I site producing two fragments of 263, and 133 bp. To ensure the results to be verified, we used sequenced genomic DNAs as positive controls in our assays.Genotyping was confirmed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis according to the protocol described previously Statistical Package for Social Sciences-SPSS for Windows . Hardy-Weinberg equilibrium was assessed by chi-square analysis. Differences in enumeration data between the cases and the controls were analyzed using the Chi-square test. Differences in distributions of genotypes and alleles between the cases and the controls were analyzed using Chi-square test. Allele frequencies distribution was analyzed by 2×2 contingency tables using a 5% level of significance. Logistic regression analysis was used to estimate the odds ratio (OR) and its 95% confidence interval (CI) as a measure of the association between polymorphism of CYP2C19 and risk of OSCC. We performed the gene-environmental interaction analysis according to the protocol described on the website http://jxzy.smu.edu.cn/151/PrjFile/lxb/showdown.asp?soft_id=244.To test the hypothesis that the frequency of the CYP2C19*3 in the OSCC patients (7%) is more than that in the control subjects (2%). It was estimated that a total of 700 subjects would be needed to ensure a power of 80% to detect a 5% difference between the 2 groups using a 2-tailed test, with a sampling ratio of case: control group at 1∶1, bilateral risk set at 5%. Data analysis was performed using the computer software P>0.05). However, there were significant differences in smoking, drinking, fruit and vegetables intake, prolonged use of wood or charcoal as sources of fuel for cooking and heating, and family history of cancer between the cases and the controls .General characteristics of the study population are presented in CYP2C19*3 A allele was significantly higher in OSCC patients than in controls . The CYP2C19*3 AG+AA genotype was significantly more prevalent in OSCC patients .The frequency of the P = 0.009; By univariate analysis, all these environmental factors including smoking, drinking, <2 portions/day of fruit and vegetables intake, and excessive smoke inhalation were associated with OSCC, and there were significant interactions between CYP2C19*3 polymorphism and these environmental factors have a higher risk of OSCC compared with GG genotype carriers. Among participants carrying CYP2C19*3 GG genotypes, drinking was associated with about 5.603-fold higher risk . However, drinking and carrying CYP2C19*3 A allele (AA or AG genotype) would be associated with an 8.747-fold risk for OSCC  when compared with non-dinking CYP2C19*3 GG genotypes. These results indicates there was a significant interaction between CYP2C19*3 and dinking on the OSCC.In the present study, we found participants who carried the In addition, we also found that for the CYP2C19*3 A allele carriers, smoking, less than 2 portions per day of fruit and vegetables intake, and prolonged use of wood or charcoal as sources of fuel for cooking and heating  increase a 11.38-fold, 7.29-fold, and 9.90-fold risk for OSCC, respectively. However, by multiple logistic analysis, these interactions did not remains significant.CYP2C19*3 polymorphism and OSCC in Chinese people. There is significant synergetic effect between CYP2C19*3 polymorphism and drinking on the risk factor for OSCC.In conclusion, we found a significant association between the


The search for genes with a positive influence on physical fitness is a difficult process. Physical fitness is a trait determined by multiple genes, and its genetic basis is then modified by numerous environmental factors. The present study examines the effects of the polymorphism of creatine kinase (CKM) gene on VO2max – a physiological index of aerobic capacity of high heritability. The study sample consisted of 154 men and 85 women, who were students of the University School of Physical Education in Poznań and athletes practicing various sports, including members of the Polish national team. The study revealed a positive effect of a rare G (NcoI−) allele of the CKM gene on maximal oxygen uptake in Caucasian women practicing sports requiring aerobic and anaerobic exercise metabolism. Also a tendency was noted in individuals with NcoI−/− (GG) and NcoI−/+ (GA) genotypes to reach higher VO2max levels. Creatine N-phosphotranspherase, also known as creatine kinase (CK) or creatine phosphokinase (CPK) plays a crucial role in the homeostasis of cellular ATP by catalyzing the conversion of creatine and consuming adenosine triphosphate (ATP) to create phosphocreatine and adenosine diphosphate (ADP). A high cellular level of creatine kinase with high energy demand, e.g. in striated and non-striated muscles, permits a fast regeneration of ATP supplies, which are the basic source of energy in biochemical processes. CK is found in large volumes in muscle cells. During exercise microleaks and microdamages occur in the myocellular membrane, through which the enzyme enters the bloodstream. Its blood level is indicative of damage of muscle cells – exercise-induced or due to myacardial infarction or ablation .In humans four genes encode subunits of five known types of CK isoenzyme. The muscle type subunit CKM and the brain type subunit CKB form CKMM and CKBB homodimers or a CKMB heterodimer. Their expression is tissue-specific and their activity depends on the demand of individual structures in the cytoplasm: CKMM protein and small amounts of CKMB are found in muscles; CKMB is most active in the heart, while CKBB protein is active in the brain and to some extent in muscle . There aThe genes encoding the particular subunits are located on different chromosomes: CKB on 14q32, CKM on 19q13.2-q13.3, Scmit-CK gene on 5q13.3, and Umit-CK on 15q1 . The subSo far studies on the CKM gene variants have indicated the presence of multiple polymorphisms, from which two (RFLP) for the NcoI and TaqI endonucleases were examined in view of their association with physical fitness. Both polymorphisms are located near the poly(A) tail at 470 bp and 1119 bp, respectively. The TaqI polymorphism is located in codon 463 and does not cause changes to the amino acid sequence .The present study attempts to analyze the restriction site polymorphism at 1449 of the 3′UTR region of the CKM gene recognized by NcoI, resulting from A>G substitution. A more frequent allele here is the wild-type NcoI+ with a restriction site. In their analysis of association of this polymorphism with an improvement of cardiorespiratory fitness estimated with VO2max after 20 weeks of training, The study was carried out on a group of competitive athletes practicing various sport disciplines, representing different sport levels, including representatives of Polish national teams and students of the University School of Physical Education in Poznan, both actively practicing sports, as well as those less active. The study was approved by the Poznan University of Medical Sciences Bioethics Committee, Poland, No 1060/05. Participants were informed about the aim and possible hazards of the analysis and each participant signed a written consent form.The group of 239 Caucasians (154 men and 85 women) aged 18–26 years was subjected to physiological and genetic analyses. All statistical analyses were performed separately for men and women.In order to verify the effects of the analysed gene polymorphism on maximal oxygen uptake, depending on the level of physical activity, the participants were then divided into athletes (119 men and 37 women) and non-athletes (35 men and 48 women). Additionally, the athletes were then subdivided into three subgroups classified by the type of exercise metabolism predominating in the discipline they practiced: (i) Sp-St - speed and strength athletes (practicing disciplines with predominance of anaerobic energy metabolism); (ii) E-Sp-St - speed endurance and strength endurance athletes (practicing disciplines requiring both anaerobic and aerobic metabolism); and (iii) E - endurance athletes (practicing disciplines dominated by aerobic energy metabolism). The division of sport disciplines was based on the classification system developed by Bellotti et al. (1978). The Sp-St subgroup contained individuals practicing sprints, long jump, high jump and discuss throw; the E-Sp-St subgroup comprised individuals practising field hockey, tennis, rugby, soccer, volleyball, basketball, handball, boxing, kickboxing, canoeing and rowing; while the E subgroup included triathlonists, medium and long-distance runners, long-distance swimmers, race walkers, skiers and mountaineers.Genetic analyses were conducted in the Laboratory of Genetic Analyses at the University School of Physical Education in Poznań, certified by ISO 9001:2008 standards (no. 69178-2009-AQ-POL-RvA). DNA for genetic analyses was isolated from 5 ml of peripheral blood collected from the participants onto anticoagulant (EDTA). DNA isolation was performed using guanidine isothiocyanate  method. An 3′ UTR NcoI CKM polymorphism (1170 bp) was genotyped by PCR-RFLP analysis. DNA was amplified in a volume of 20 μl. Genomic DNA from each examined individual was placed in a separate test tube in the amount of 4 μl (200 ng) and 16 μl reaction mixture was added, containing 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl2, 0.25 mM dNTP, 7.5 pmol each, primer and 0.5 unit of Taq polymerase . The primers sequence was: Forward - gTg Cgg Tgg ACA CAg CTg CCg and Reverse - CAg CTT ggT CAA AgA CAT TgA gg . The 30 The polymorphism 3′ UTR NcoI CKM gene was genotyped by PCR – RFLP method with NcoI enzyme in the condition recommended by the supplier . The digested products were then electrophoresed in 1.5% agarose gel.In order to determine maximal oxygen uptake the direct method was used during exercise tests on a treadmill . During each test, the composition of inhaled and exhaled air  was analysed by an Oxycon Mobile spiroergometer  and the heart rate (HR) was monitored using a pulsometer . The exercise tests were carried out on a treadmill with increasing loads, starting from a running speed of 8 km/h, increasing the load by 2 km/h every 3 min, until the moment of maximum individual load was reached. Physiological analyses were conducted in the Laboratory of Functional Examinations at the University School of Physical Education in Poznań, certified by ISO 9001:2008 standards (no. 69178-2009-AQ-POL-RvA).2 test. The Bartlett test was performed to determine the homogeneity of variance. The association between analysed polymorphisms and maximal oxygen uptake (VO2max) was verified using the ANOVA one-way analysis of variance – the parametric test t. Statistical calculations were performed in the Computer Laboratory of the Faculty of Animal Breeding and Biology at the Poznań University of Life Sciences, with the use of SAS statistical software ver. 9.1 (USA). Statistically significant differences in maximal oxygen uptake between the given genotypes were underlined in tables as a – at p<0.05, A – at p<0.01.The consistency of the maximal oxygen uptake values and genotype distribution fit to the Hardy–Weinberg principle were verified with the χAn analysis of association was carried out using results of physiological and genetic studies of 239 subjects. Smokers and subjects outside the age brackets of 18–26 years and normal BMI range were excluded. Individuals for whom there were doubts as to whether their fitness test (treadmill test) results were not maximal due to their low motivation were also excluded from the study protocol. The study sample consisted of 154 men  and 85 women . All subjects were students of the University School of Physical Education, and thus even the non-training controls displayed a higher than average level of physical activity. The subjects trained endurance sports such as the marathon, rowing, kayaking and triathlon; sports involving both aerobic and anaerobic exercise metabolism – field hockey, volleyball, football, handball, rowing; and speed-strength sports such as bodybuilding, track sprints, long jump, and high jump.2max) directly with the use of an Oxycon Mobile ergospirometer with constant data transfer from the analyzer to a PC registering changes of such physiological variables as the heart rate (HR), inhaled and exhaled air volume  and respiratory exchange ratio (RER).The subjects performed a treadmill test to measure their maximal oxygen uptake levels . The homogeneity of variances was checked with the Bartlett’s test. 2max levels for polymorphic variants of each studied gene. The analysis of variance did not show statistically significant differences between mean values of the recorded maximal oxygen uptake in groups represented by genotypes GG (NcoI −/), GA (NcoI −/+) and AA (NcoI +/+).The association of the 3′ UTR NcoI −/), GA (NcoI −/+) and AA (NcoI +/+).The analysis of variance did not show statistically significant differences between mean values of the recorded maximal oxygen uptake in groups represented by genotypes GG  for individual polymorphisms in the two subgroups is shown in In order to examine possible differences between the values of maximal oxygen uptake for different genotypes with regard to the level of physical activity the sample was divided into athletes and non-athletes. The distribution of the genotypes and VOThe analysis of variance did not show statistically significant differences between mean values of maximal oxygen uptake in groups represented by genotypes GG, GA and AA.2max levels reached by subjects with different genotypes of the studied polymorphisms in relation to the type of exercise metabolism prevalent in particular sports. 2max values for the polymorphisms of the studied genes in the subgroups practicing speed-strength sports, speed endurance and strength endurance sports, endurance sports and in untrained controls. The analysis of variance revealed in several cases significant differences in VO2max, depending on the genotype. There was a significant difference in VO2max between female athletes with AA and AG genotypes practicing speed endurance and strength endurance sports, and subjects with AA and GG genotypes (p ≤ 0.01).The obtained results were also analyzed with regard to VOThe analysis of variance did show statistically significant differences between mean values of the recorded maximal oxygen uptake between either AA and GA or AA and GG genotypes in the female endurance-speed-strength subgroup.The analysis of variance did show statistically significant differences between mean values of maximal oxygen uptake between either AA and GA or AA and GG genotypes in the female E-Sp-St subgroup.Athletes feature a considerable inter-individual variability affected by a number of environmental  as well as genetic factors . GeneticThe inclusion of the genetic component in anatomical, anthropological, biochemical and physiological analyses makes the study of predispositions to practice a given sport more complete. However, an analysis of complex traits being the sums of numerous genes with little individual effect is not easy, and interpretation of results of such an analysis may lead to false conclusions, e.g. due to the small sample size. The perplexity of analysis of association of candidate genes with a complex trait such as physical fitness can be illustrated by ambiguous or even strikingly different study results attained by various research teams examining the genetic profiles of physical abilities in groups of subjects with different levels of physical activity and of different ethnic background.The present study focused on the effects of a very interesting polymorphism in the CKM gene. Physical fitness was determined by the level of VO2max, which is a good and fairly versatile physiological index of general physical fitness, especially of aerobic capacity. Moreover, maximal oxygen uptake features relatively the highest heritability (h2 = 0.59–0.87) among physical fitness variables, and its value in the age bracket represented by the study sample (18–26 years) reaches its maximum and remains relatively constant . This isTo the best of our knowledge the CKM polymorphism has not been studied yet among the Polish population. Our study is arguably the first completed research in Poland aimed at seeking the genetic determinants of physical fitness in Caucasian Polish athletes.The results of physiological and genetic analysis were checked for conformity with the Hardy-Weinberg equilibrium model. Both VO2max as well as the majority of examined polymorphisms conformed with the Hardy-Weinberg distribution.So far the RFLP NcoI in the 3′UTR of the CKM gene has been shown to be correlated with VO2max and its changes following 20 weeks of training . In biocThe analysis of association between the CKM NcoI polymorphism and maximal oxygen uptake revealed statistically significant differences (p = 0.01) between women with the AA genotype (NcoI+/+) and other genotypes  in a subgroup of athletes practicing sports involving aerobic and anaerobic exercise metabolic patterns. The mean VO2max was, in fact, the lowest for the AA (NcoI+/+) genotype, and the highest for the GG (NcoI−/−) genotype. A tendency to reach the highest VO2max levels by individuals with the GG or AG genotypes can be observed in studies with regard to the sex and genotypes and in the majority of subgroups. It can be concluded that the rare G (NcoI−) allele  has a positive effect on the VO2max level. The exception are men practicing endurance sports, among whom the GG genotype was the lowest. The observed higher VO2max for the GG (NcoI−/−) genotype does not correspond with other researchers’ findings. An association between the NcoI polymorphism of the CKM gene with maximal oxygen uptake was found in women practicing sports involving both aerobic and anaerobic exercise metabolism. A tendency was observed among individuals with the NcoI−/− (GG) and NcoI−/+ (GA) genotypes to achieve higher VO2max levels.


BsmI, ApaI or TaqI) with various clinical, biochemical, and serological factors in a homogenous group of 143 Caucasian patients with PBC. Control group comprises 306 DNA samples from umbilical cord blood of healthy newborn children. When compared to controls, we observed a significant dominance of the b allele in the BsmI  and t allele in the TaqI  in patients with PBC. Moreover the BsmI and TaqI polymorphisms were associated with the presence of advanced fibrosis/liver cirrhosis at the diagnosis of PBC. Pairwise linkage disequilibrium (LD) calculations proved that the analyzed SNPs are within an LD block (100% of LDs were D'>0.9). Our study showed, for the first time, that the analyzed polymorphisms of VRD may exert an effect on a natural history of PBC.Primary biliary cirrhosis (PBC) is a chronic cholestatic liver condition characterized by the immune-mediated damage of the intrahepatic bile ducts. Polymorphisms of vitamin D receptor (VDR) are considered to contribute to its pathogenesis however their incidence varies in different populations and their potential association with the course of the disease has not been studied. In this paper we investigated the incidence and correlation of three VDR polymorphisms ( Primary biliary cirrhosis (PBC) is a chronic cholestatic liver condition  which ma2D3), apart from its central role in calcium and bone metabolism, possesses immunomodulatory properties and represents an important component of the immune system homeostasis [2D3 can influence the risk of various autoimmune conditions, such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic sclerosis, or inflammatory bowel disease [A fat-soluble secosteroid hormone 1,25-dihydroxyvitamin D3 eostasis . Many ob disease –21.2D3 exerts the biological effects through its own nuclear hormone receptor, the vitamin D receptor (VDR), which belongs to the family of transacting transcriptional regulatory factors [BsmI), rs7975232 (ApaI) (both in intron 8), and rs731236 , discovered at the 3′ end of the VDR gene, have been analyzed in the past but their effects on VDR function still remain poorly understood [1,25(OH) factors . VDR is  factors . Recent derstood –26. Theiderstood –30 but nIn this study we investigated the prevalence of VDR polymorphisms in a homogenous cohort of well-characterized Polish patients with PBC. We also looked at a potential effect of these polymorphisms on the clinical and laboratory features in analyzed cohort of patients.One hundred and forty-three patients  were enrolled in this study. All patients met the criteria for the diagnosis of PBC recently introduced by EASL Guidelines  accordinUmbilical cord blood samples from 306 healthy newborn children served as controls. Data of analyzed subjects are summarized in DNA from peripheral blood mononuclear cells was isolated using the DNeasy Blood & Tissue Kit (Qiagen). Oligonucleotide primers and TaqMan probes for VDR polymorphisms  were designed and synthesized by Applied Biosystems . The fluorescence data were analyzed with allelic discrimination 7500 Software v.2.0.2.P  value < 0.05 was consider considered to be statistically significant.Data are shown as means and standard deviations. All statistical analyses  were carried out using StatView software . The genotype and allelic frequencies were compared between patients and controls using Fisher's PLSD test. The analysis of genotype frequency within PBC patients in regards to the clinical characteristics was performed using Fisher's PLSD test. Linkage disequilibrium (LD) for rs7975232, rs15444410, and rs731236 for PBC patients was analyzed with the software Haploview 4.2. BsmI; rs7975232-ApaI) and one in exon 9 (rs731236 = TaqI) were analyzed. A significant difference in genotype frequency between patients with PBC and healthy controls at the BsmI and the TaqI polymorphisms but not at the ApaI polymorphism was found. The X2 value and the prevalence of each genotype are shown in BB) genotype at the BsmI polymorphism between PBC patients and controls. AA (BB) genotype was present less frequently among the patients with PBC . By contrast, at the TaqI polymorphisms the CC (tt) genotype was represented more frequently  and correspondingly, the frequency of TT (TT) genotype decreased significantly in patients with PBC in comparison to the controls . We found no difference at the polymorphism.The following two VDR gene polymorphisms in intron 8  and t allele in the TaqI  in PBC patients in comparison to controls   . Both lastology) .D' > 0.9) (Pairwise linkage disequilibrium (LD) calculations confirmed that the analyzed SNPs are within a LD block (100% of LDs were ' > 0.9) .BsmI, ApaI, and TaqI polymorphisms and the susceptibility for PBC and severity of the disease in a homogenous group of Polish patients. We have found that BsmI polymorphism occurred significantly more commonly in patients with PBC than in controls. These findings are consistent with the ones by Vogel et al. [b” allele [TaqI polymorphism in patients with PBC, what is again in agreement with the observation by Vogel et al. [t” allele as well as “tt” genotype, but in the study by Vogel “Tt” genotype was predictive for PBC. Additionally, the study from Tanaka et al. indicated the high prevalence of ApaI in PBC [In this study we have analyzed the association between l et al.  and Fan l et al. , whereas” allele , 34. Morl et al. . In our I in PBC , but ourOne may say that in the era of genomewide association studies which involve very large cohorts of subjects analyses aimed at looking at selected polymorphisms in smaller groups have lost their significance. In the context of PBC, four GWASs have been performed and included homogenous groups from Northern American, Italian, mostly Northern American, and British patients, respectively. The first one suggested the role of polymorphisms of gene encoding IL-12 alpha and beta chains . FurtherThese results clearly show that each new GWAS adds new susceptibility loci identified in analyzed populations. Thus the fact that VDR polymorphisms were not found in already performed GWAS does not definitely preclude their role in the susceptibility to PBC.BsmI and TaqI could be associated with the susceptibility to liver cirrhosis or advanced fibrosis in these subjects which is a new finding. However we found no significant correlations between the cholestasis or the prevalence of autoantibodies and the presence of analyzed polymorphisms.In addition, we have looked at the potential correlation between polymorphisms of VDR gene and clinical and laboratory findings in analyzed patients. We noticed that the polymorphisms of BsmI and TaqI polymorphisms somehow predisposes to more severe liver injury, independently of the biochemical measurements of cholestasis or autoimmune process. Other studies suggested that VDR polymorphisms can contribute to the development of osteoporosis in patients with PBC [Little is known on how the genotype variety of VDR gene is linked to clinical course of the disease as previous studies focused mostly on the prevalences of each polymorphisms in PBC. It is possible that the allelic variety of with PBC ; howeverwith PBC .TaqI polymorphism results in a silent mutation in exon 9 and the location of the BsmI and ApaI is intronic, thus probably these polymorphisms are anonymous [BsmI and TaqI are genetic markers of the presence of other, so far unknown functional sequence variations nearby in the VDR gene which is in linkage disequilibrium with identified alleles [Interpretation of the significance of polymorphisms in the VDR gene is hindered by the fact that the functional effects of allelic variations are poorly understood. Indeed, VDR polymorphisms are considered to be associated with an increased risk of several autoimmune diseases, but so far no correlation has been identified with functional phenotypes . It can nonymous . Thus it alleles , 32. Bec2D3 may be one of possible explanations on how VDR polymorphisms can contribute to the pathogenesis of PBC. 1,25(OH)2D3 activates monocytes and macrophages and acts as a positive regulator of the development of Th2 cells and production of anti-inflammatory interleukin (IL)-4 and transforming growth factor β [γ, tumor necrosis factor α, and β) [2D3-dependent signaling pathways caused by the VDR polymorphisms might skew the immune response to the Th1 pathway, contributing to the development of PBC [The immunomodulatory properties of 1,25(OH)factor β , 39. Mor, and β) –42. PBC , and β) ; therefot of PBC .Other mechanism, in which VDR polymorphisms can be involved in the pathogenesis of PBC, is a role of VDR as a receptor for a lithocholic acid (LCA) as well as an endocrine receptor for vitamin D signaling. LCA is a secondary bile acid produced by intestinal bacteria from primary bile acids that may escape reabsorption in the intestine and can accumulate to high levels in the enterohepatic circulation of some subjects . LCA is  BsmI and TaqI polymorphisms of VDR with the susceptibility to PBC in a cohort of Polish patients. Also we have shown that these patients have an increased risk of liver cirrhosis and advanced fibrosis which is a novel finding of this study. Further studies focused not only on the identification of risk polymorphisms involved in development of PBC but also on the mechanism in which they lead to development and the course of the disease are warranted.In summary, in this present study we have shown the association of


SMAD7, was identified by two recent genome-wide association (GWA) studies to be strongly associated with the risk of colorectal cancer (CRC). However, the following replication studies yielded conflicting results.A common genetic variant, rs4939827, located in P for heterogeneity <0.1). By stratified analysis, we revealed that ethnicity, sample size, and tumor sites might constitute the source of heterogeneity. The cumulative analysis suggested that evident tendency to significant association was seen with adding study samples over time; whilst, sensitive analysis showed results before and after removal of each study were similar, indicating the highly stability of the current results.We conducted a case-control study of 641 cases and 1037 controls in a Chinese population and then performed a meta-analysis, integrating our and published data of 34313 cases and 33251 controls, to clarify the relationship between rs4939827 and CRC risk. In our case-control study, the dominant model was significant associated with increased CRC risk . The following meta-analysis further confirmed this significant association for all genetic models but with significant between-study heterogeneity (all Results from our case-control study and the meta-analysis collectively confirmed the significant association of the variant rs4939827 with increased risk of colorectal cancer. Nevertheless, fine-mapping of the susceptibility loci defined by rs4939287 should be imposed to reveal causal variant. Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer mortality worldwide SMAD7), a strong candidate gene in the famous transformation growth factor-β (TGF-β) pathway. SMAD7 acts as an intracellular antagonist of TGF-β signaling by recruiting SMURF to receptors for inactivation. Perturbation of SMAD7 and suppression of TGF-β signaling has been documented to involve in CRC Genome-wide association (GWA) study has greatly contributed to identification of common genetic variants associated to common disease without prior knowledge of gene function. Several resent GWA studies have reported multiple novel susceptibility loci to colorectal cancer In this study, a total of 641 new CRC cases and 1037 cancer-free controls were enrolled from between 2009 and 2011 from Tongji Hospital of Huazhong University of Science and Technology, Wuhan, China. Cases had been histopathologically confirmed with primary colorectal cancer and had not received any treatment prior to blood samples collection. Controls were randomly selected from a subject pool of individuals who participate in health check-up programs at the same hospital in the same time period as the patients were enrolled. Controls were frequency matched to patients by age (±5 years) and gender. All subjects were unrelated ethnic Han Chinese living in Wuhan region. At recruitment, a 5-ml peripheral venous blood sample was collected from each subject after written informed consent was obtained. This study was approved by ethnics committee of Tongji Hospital of Huazhong University of Science and Technology.Genomic DNA was extracted from 5-mL of peripheral blood sample using the RelaxGene Blood System DP319-02  according to the manufacturer's instructions. The genotypes of rs4939827 were determined by using the TaqMan SNP Genotyping Assay  on a 7900HT Fast Real-Time PCR System . For quality control, 5%duplicated samples were randomly selected for to assess the reproducibility, with a concordance rate of 100%2χ test, fisher exact test, and t test were employed to evaluate the differences in distribution of demographic characteristics and genotypes between case and control groups, where appropriate. Goodness-of-fit χ2 test was adopted to assess Hardy-Weinberg Equilibrium (HWE) in the controls. Unconditional multivariate logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the effect of rs4939827 genotypes on CRC risk, after adjusting for age and sex. To avoid the assumptions of genetic models, additive and dominant models for rs4939827 were also assessed. All statistical analyses were performed with the SPSS 12.0 software. A value of P<0.05 was considered representative of statistical significance.Pearson To further investigate the association between rs4939827 and CRC risk, a meta-analysis based on the published studies was carried out according to the guidelines of Preferred Reporting Items for Systemic Reviews and Meta-Analyses statement (PRISMA) Q statistic to assess heterogeneity (heterogeneity was considered significant at P<0.1) 2I metric was applied to quantify heterogeneity irrespective of numbers of studies  The following data were extracted by two independent authors (B. Zhu & Q. Song): first author's last name, country of origin, publication year, predominant ethnicity of participants, sample size, study method and design, source of control groups , genotyping method. Counts of alleles and genotypes in cases and controls were extracted or calculated from published data. Pooled frequency of the T allele in various ethnic populations was estimated using the inverse variance method previously described by Thakkinstian et al P = 0.748) and age (P = 0.119) between case and control group. Of Cases, 39% had colon cancer and 61% had rectum cancer. Regarding tumor state, 12.9%, 35.6%, 35.4% and 16.1% of cases were classified as Duke's A, B, C and D stage at the time of diagnosis, respectively.A total of 641 incident cases of colorectal cancer and 1037 frequency-matched controls were enrolled in this study. As shown in P = 0.214). Significant difference in genotype distribution was observed between cases and controls . In the multivariate logistic regression model, individuals with the CT genotype had a significant, 57% increased risk of CRC  compared to those with the CC homozygote. Due to the low frequency of the TT genotype (3.2% in controls and 1.6% in cases) in this study population, a dominant model was perform, by combining the TT with the CT into an T carrier (TT plus CT) group, and result showed that the T carrier also present significantly increased risk, compared with those carrying the CC genotype . In the allelic model, T allele carriers also showed significantly increased risk compared to those with the C allele . In the additive model, per-T allele similarly conferred an OR of 1.27  (Genotypes in the controls conformed to Hardy-Weinberg equilibrium ( = 0.01) .We then stratified data according to the pathological factors under the dominant model. The CT plus TT genotypes were both associated with increased risk of colon and rectal cancers. Interestingly, the effect of the CT plus TT genotypes was larger in colon cancer  than that in rectum cancer . Regarding the Duke's stage, the CT plus TT genotypes were associated with increased risk in early stage  but not in advanced cancer . Under random-effects model, the pooled frequency of the T allele was 51.2%  in European controls, which was markedly higher than that of 23.4% in Asian controls (Both significant between-study heterogeneity were observed in European and Asian groups (4%–28.3%). These pP for heterogeneity <0.05), and ORs for all genetic models were pooled under random-effects model. In allelic model, the T allele conferring a pooled OR of 1.18 compared to the C allele .As reflected by the funnel plot . and EggSMAD7,which encodes a inhibitory SMAD protein that function as a negatively feedback regulator of TGF-β signals rs4939827 located at 18q21 was revealed to be associated with CRC risk by two GWA studies, but inconsistent results have been reported by multiple following replication studies. In this study, we initially found a significant association between the variant 4939827 and increased risk of CRC in a case-control set of a Chinese population. Then the following meta-analysis, first to integrate GWA and replication data from 25 case-control studies of 34313 cases and 33251 controls, consistently indicated the significant association of rs4939827 with the risk of CRC. This significant association was further confirmed by cumulative meta-analysis, presenting the effect of the variant got increasingly significant with each accumulating of more data over time. rs4939827 is located in intron 3 of Nevertheless, the obvious evidence of between-study heterogeneity in this meta-analysis should be issued. We have applied a comprehensive stratified analysis to interrogate the potential source of heterogeneity. After stratifying by ethnicity, heterogeneity was largely reduced in Asian, reflecting ethnicity could partly explain the heterogeneity. The further supports of that came from the evidence that various manners the T variant likely act in and different allele frequencies between European and Asian populations. When stratified by tumor sites, rectum cancer subgroup did not show heterogeneity anymore, suggesting tumor sites might also be a potential source of heterogeneity. Additionally, significant association only presented for rectum cancer, which was inconsistent with our case-control study, possibly due to our small sample size for stratification by tumor sites. Regarding sample size, heterogeneity was almost removed in small sample studies but not large sample subgroup, possibly due to more complex confounding factors introduced into large sample. Significant association remained in large sample studies for all genetic models, whereas only the recessive model showed significant result in small sample subgroup, reflecting the limited power of small sample size to detect the modest effect of the variant. Taken together, we revealed that the ethnicity, tumor sites, and sample size might constitute source of heterogeneity in this meta-analysis. Whilst, the significant association of rs4939827 presented in the subgroup of replication studies, consistent with the result from GWA study subgroup, suggested this meta-analysis succeed in amplifying power to detect the modest effect of this variant by pooling data across studies. Furthermore, the sensitivity analysis and publication bias assessment indicated the current results from this meta-analysis were stable.Despite the clear strengthen of this study that applied a comprehensive analysis strategy, several limitations should be Figured out. First, the sample size of our case-control study was relatively small. Nevertheless, the following meta-analysis with enough power has drawn the consistent result with our case-control study. Second, the analysis of separate effect for colon or rectum cancer conferred limited power, and more studies are needed. Additionally, CRC is a complex trait corporately influenced by genetic and environmental factors; however, lacking the environment data limited us to further assess gene-environment interaction.In conclusion, our study in a Chinese population and this meta-analysis collectively confirm the significant association between SNP rs4939827 and the colorectal cancer risk in European and Asian populations. However, although a novel SNP in highly LD with rs4939827 has been proposed to be causal, further fine-mapping of the CRC susceptibility loci tagged by rs4939827 is warranted to uncover more causal variants, especially for the low-frequency or rare functional variants.Figure S1Flow chart of study selection.(TIF)Click here for additional data file.Figure S2Pooled frequency of T allele in European and Asian population.(TIF)Click here for additional data file.Figure S3Funnel plot of publication bias under allelic model.(TIF)Click here for additional data file.


XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk.Recently, there have been a number of studies on the association between XRCC1 polymorphisms  and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used.A meta-analysis was performed to examine the association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses  and Asian subgroup analyses . No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found.Significant association between XRCC1 Arg399Gln polymorphism might be associated with elevated childhood ALL risk among Asian population.The meta-analysis results suggested that  While survival rates for childhood acute lymphoblastic leukemia (ALL) have been improved significantly over the past 50 years, ALL is still the most common pediatric cancer in developed countries with high incidence and mortality As a complex and multifactorial process, leukemogenesis is still not fully understood. It is widely known that dysregulated immune response to infection may be a cause of childhood ALL To date, the candidates for childhood ALL susceptibility genes have been categorized into those coding for carcinogen metabolism enzymes, folate metabolism enzymes, DNA repair proteins, and others XRCC1), located on chromosome 19q13.2–13.3, with 33 kilobases in length, is one of the most important proteins in base excision repair (BER) XRCC1 gene reported in the dbSNP database (http://www.ncbi.nlm.nih.gov/SNP). Nevertheless, only three genetic changes have been extensively studied including Arg194Trp on exon 6 , Arg280His on exon 9 , and Arg399Gln on exon 10 . There have been a number of studies on the association between XRCC1 polymorphisms and childhood ALL risk XRCC1 variants  on childhood ALL risk, we conduct a meta-analysis of all eligible studies to resolve this pivotal issue.X-ray repair cross-complementing group 1 (XRCC1” or “X-ray repair cross-complementation group 1”), covering all papers published before November 30, 2011. All eligible articles were retrieved and their references were searched simultaneously to find other relevant articles. Inclusion criteria was defined as follows: (1) case-control studies evaluating the association between XRCC1 polymorphisms and childhood ALL risk; (2) studies based on unrelated individuals; (3) sufficient published data available to estimate an odds ratio (OR) with 95% confidence interval (CI). We excluded studies that were not full-length publications articles or letters in peer-reviewed English journals. When the same patient population was included in different articles, the one with the largest population of participants or the most recent one was selected.Computer searches of PubMed, EMBASE, Medline, Google Scholar and Cochrane Library were performed by two authors independently using the following key words (“childhood acute lymphoblastic leukemia” or ”childhood ALL”)and with the corresponding 95% CI for each study. The OR and its 95% CI in each comparison were assessed in additive , dominant (aa+Aa versus AA), and recessive (aa versus Aa+AA) genetic models. Heterogeneity among studies was tested by chi-square-based Q test, and I2 statistics was calculated to quantify the proportion of the total variation due to heterogeneity The strength of With our search criterion, a total of eleven full-text articles XRCC1 Arg399Gln polymorphism and childhood ALL risk, and the heterogeneity test were shown in OR = 0.008, P = 0.384 for heterogeneity) . We did not observe any significant association in any genetic model among other subgroups. Moreover, meta-regression analysis revealed that ethnicity was a significant source of between-study heterogeneity (P = 0.007).The results of the associations between ogeneity). We alsogeneity) . No signOR = 0.709; Dominant model: OR = 1.125, 95% CI 0.805–1.574, POR = 0.490; Recessive model: OR = 1.203, 95%CI 0.357–4.055, POR = 0.765) and Arg194Trp polymorphism. Subgroup analysis based on ethnicity also showed no significant association between the two SNPs and childhood ALL risk.There was no statistical difference in all contrasts of genotypes for Arg280His polymorphism ; Arg194Trp polymorphism additive model , dominant model , recessive model   . A randoInfluence analysis was performed to assess the influence of each individual study on the pooled OR by sequential omission of individual studies. The results suggested that no individual study significantly affected the pooled ORs .Publication bias was examined by Funnel plot and Egger's regression test. The shapes of the funnel plot did not indicate any evidence of obvious asymmetry in additive model  and the XRCC1 plays an important role in the DNA damage repair pathway for the processing of small base lesions, which has been thought of as the predominant DNA-damage repair pathway for the processing of small base lesions derived from oxidation and alkylation damage XRCC1 genetic polymorphisms and provide the most comprehensive assessment of its association with childhood ALL risk. By critically reviewing 7 studies on XRCC1 Arg399Gln polymorphism , 3 studies on XRCC1 Arg280His polymorphism , and 6 studies on Arg194Trp polymorphism , we performed a meta-analysis to indicate that the polymorphisms in XRCC1 Arg399Gln was significantly associated with risk of childhood ALL. However, we did not observe associations of XRCC1 Arg280His polymorphism and Arg194Trp polymorphism with childhood ALL risk.XRCC1 variant 399Gln allele was 28.99% . No association was detected in Caucasians, Metizo and mixed populations, while increased risk was found in Asian population carrying variant 399Gln allele homozygote, and it should be further investigated in large scale Asian populations.This study showed that the mean frequency of the s 28.99% . PreviouDespite lots of investigations in many aspects of childhood ALL, little attention has been paid to its pathogenesis, particularly with respect to genetic susceptibility. Several reports have demonstrated the association between some DNA repair gene variants and childhood ALL, so the possible relationship between polymorphisms of DNA repair genes and childhood ALL may be helpful in understanding the pathogenesis of childhood ALL and the prevention of this disease. Our results suggest that the risk of childhood ALL may be associated with DNA repair mechanisms. XRCC1 polymorphisms may be used as an important predictive factor, and ethnic background might have an impact on the results in the studies of its polymorphisms in childhood ALL. Analysis of these polymorphisms, particularly XRCC1 codon 399 Arg/Gln may help in identifying individuals at risk of developing ALL and providing an essential information source for future improvement of ALL treatment.XRCC1 variants and risk by subtype. Second, specific environmental and lifestyle factors may alter those associations between gene polymorphisms and cancer risk. Evidence supports that there is no association between Gln/Gln genotype of Arg399Gln and bladder cancer risk in total population, but it is associated with a decreased risk of bladder cancer among ever smokers XRCC1 gene polymorphism and childhood ALL risk was analyzed without consideration of gene–gene and gene-environment interactions because of the lack of sufficient data, which should be further investigated. Third, the Funnel plot did not reveal any evidence of obvious publication bias, while there is still a possibility that our meta-analysis was biased toward a positive result since negative findings were likely to be unreported.Although our result is suggestive, there are still some limitations in this meta-analysis. First, heterogeneity among the studies, resulting from different sources of controls, matching criteria of age and gender or some other factors, may influence the results of this analysis. The matching criteria of the control group, such as age, gender, and environment exposures, are different between studies. Furthermore, childhood ALL is heterogeneous considering its underlying cellular and molecular biology, so subtypes of B- or T-cell precursor ALL may not be suspected to share a common etiology. To date none of the studies have examined the relationship between XRCC1 399Gln might be a susceptibility allele for childhood ALL. However, we could not observe any association of XRCC1 Arg194Trp and Arg280His with childhood ALL. We have searched as many publications as we could by means of various searching approaches, comprehensively assessed publication biases and pinpointed the potential sources of heterogeneity via subgroup and sensitivity analysis. However, these results may be biased by the relatively small number of subjects, and therefore need to be validated by larger studies and subsequent update of the current meta-analysis. In order to understand the mechanisms underlying childhood ALL better, future research should be considered and investigated.In summary, it is a worthy and meaningful enterprise to search for polymorphic variants influencing the risk of childhood ALL. This meta-analysis suggests that Table S1Frequencies of XRCC1 Arg194Trp, Arg280His and Arg399Gln allele among control population in different studies.(DOC)Click here for additional data file.


Atrial fibrillation (AF) is one of the most common types of arrhythmia in humans. Recently, many studies have investigated the relationship between human atrial fibrillation and the single nucleotide polymorphism (SNP) of rs1805127 (A>G) in KCNE1 gene, but the results were still inconsistent and inconclusive.Electronic databases and bibliographies of retrieved studies were searched. We performed a meta-analysis of ten case-control studies, including 2099 cases and 2252 controls, to evaluate the association of rs1805127 polymorphism (A>G) with the risk of AF. Random-effects model was used when the heterogeneity was obvious; otherwise, fixed-effects model was applied. Meta-regression was performed to examine potential source of heterogeneity. Egger's test and Begg's test were used to detect publication biases.heterogeneity = 0.217), heterozygote comparison , dominant model and recessive model . Meta-regression revealed that the sample size and the types of AF were the source of the heterogeneity.The results showed a significantly increased risk of AF in homozygote comparison  of KCNE1 is associated with an increased risk of AF, which suggests the rs1805217 polymorphism of KCNE1 gene may play an important role in the pathogenesis of AF. Atrial fibrillation (AF) is the most common type of sustained tachyarrhythmia in human, and the prevalence increased year by year. However, the pathogenesis of AF remains unclear. Currently, a number of studies have shown that mutations in ion channel genes may be the risk factors of AF The KCNE1 gene was first discovered by Murai in 1989To determine the association between KCNE1 rs1805127 polymorphism and the risk of AF, we performed this meta-analysis of published case-control studies to attain better results and hence more details and accurate risk estimation.We done this meta-analysis according to the PRISMA guideline (Supporting information: Inclusion criteria were as follows: (1) case-control studies; (2) investigating the association between the KCNE1 rs1805127 (A>G) polymorphism and risk of AF; (3) studies that provide detailed genotypes data  in AF cases and control groups. Exclusion criteria were as follows: (1) duplicated studies; (2) no controls; (3) no detail genotype frequencies. We did not consider unpublished reports, abstracts, comments, reviews, or editorials. Two reviewers extracted eligible studies independently according to the inclusion criteria. Disagreements between two reviewers were discussed with another reviewer till consensus was achieved.http://ihg.gsf.de/cgi-bin/hw/hwa1.p1) was used to test the Hardy-Weinberg equilibrium in the controls Data extraction was conducted independently by two authors with disagreements resolved by discussion. The following data were extracted from eligible study: the first authors' name, publication year, country where the study was conducted, genotyping methods, ethnicity, source of control, Hardy-Weinberg equilibrium (HWE), number of cases and controls, genotype frequency in cases and controls. Different ethnicities were divided into Asian and Caucasian. Source of control in the studies were defined as hospital-based (HB) and population-based (PB). An online program (Odds ratios (OR) and 95% confidence intervals (CI) were used to measure the association strength between the KCNE1 rs1805127 polymorphism and AF risk. In this meta-analysis, we evaluated the overall AF risk in four comparison models: homozygote comparison (GG vs. AA), homozygote comparison (GA vs. AA), recessive model (GG vs. GA/AA) and dominant model (GG/GA vs. AA). Subgroup analyses were carried out to explore the confounding factors: ethnicities, source of control and sample size. Sensitivity analyses were performed to identify individual study effect on pooled results and test the reliability of results.The Cochran's Q statistic was used to evaluate the heterogeneity between studies We used visual inspection of asymmetry in funnel plots, Begg's test and Egger's test to statistically potential publication bias, and a P<0.05 was considered significant Finally, 10 studies investigating the association between the rs1805127 polymorphism of KCNE1 gene and AF were identified according to the inclusion and exclusion criteria, including 2099 cases and 2252 controls heterogeneity = 0.217, heterogeneity = 0.739, heterogeneity = 0.778, heterogeneity = 0.03, In overall analysis, we found rs1805127 polymorphism was associated with increased risk of AF in all four comparisons: homozygote comparison , except for heterozygote comparison .We assessed publication bias by Begg's funnel plot and Egger's test. The results showed no evidence of publication bias (homozygote comparison: PKCNE1 gene encodes the β-subunits of the delayed rectifier potassium current channel (IKs) in human heart. The delayed rectifier potassium current channel (IKs) is important for cardiac repolarization, especially at the late phase of phase 3 of action potential, and it's closely related to action potential duration In this meta-analysis, we analyzed 10 studies including 2099 cases and 2252 controls and found a significant association between the rs1805127 polymorphism (A>G) of KCNE1 and increased risk of AF in all comparison models of overall analysis.In subgroup analyses of ethnicity, the significant association was observed in all comparisons in Asian population, but not all comparisons in Caucasian. Small sample size and limited number of studies of Caucasian in this meta-analysis  of KCNE1 gene and risk of AF, including 2099 cases and 2252 controls. There was no limitation of languages when searching, and the results showed a low chance of publication bias. Some limitation of our meta-analysis should be considered. Firstly, AF was considered as a multi-factorial disease, to achieve more precise estimate, individual data should be adjusted according to some other variables that related to risk of AF, such as family history and coronary heart disease. Secondly, as reported by Fatini In conclusion, our meta-analysis demonstrates that the rs1805127 polymorphism (A>G) of KCNE1 gene is associated with increased risk of AF; this finding suggests that the rs1805217 polymorphism of KCNE1 gene may play an important role in the pathogenesis of AF. To confirm this association, further experiment studies are warranted.Table S1PRISMA checklist.(DOC)Click here for additional data file.