TBX5) was positively associated with PR interval, QRS duration, QT interval, and common arrhythmia disorders such as atrial fibrillation (AF) and advanced atrioventricular block. However, other independent replication studies are required to validate the result. This study assessed associations between rs3825214 and ECG parameters, AF, and ventricular tachycardia (VT) in a Chinese Han population.A prolonged PR interval is a sign of increased risk of cardiac arrhythmia. Recent genome-wide association studies found that the single-nucleotide polymorphism (SNP) rs3825214 in T-box 5  and a highly significant association was detected between the G allele of rs3825214 and lone AF . We also found that rs3825214 showed a significant association with atrial-ventricular block .To assess the association between rs3825214 and AF and VT, we carried out case-control association studies with 692 AF patients (including 275 lone AF patients), 235 VT patients, and 856 controls. Genotyping was performed using a Rotor-Gene TM 6000 High Resolution Melt system. Statistical analyses of associations were adjusted for potential confounding factors. A moderate association was detected between rs3825214 and AF (Our results indicate that rs3825214 conferred a significant risk of lone AF in this Chinese Han population. Atrial fibrillation (AF) is the most common supraventricular tachycardia encountered in clinical practice, and is associated with pronounced morbidity, mortality, and socio-economic burden Ventricular tachycardia (VT), another important type of arrhythmia, is the most common cause of sudden cardiac death TBX5) gene, was positively associated with the electrocardiography (ECG) PR interval (combined P = 3.3×10−12), duration of the QRS complex (combined P = 3.0×10−13), and QT interval (combined P = 9.5×10−8) and may lead to cardiac arrhythmia such as AF and atrioventricular block (AVB) TBX5 is widely expressed in the atrial, atrioventricular node, and ventricular bundle branches, indicating that variations in TBX5 may have an important role in the pathogenesis of AF and VT Recently, genome-wide association studies found that the single-nucleotide polymorphism (SNP) rs3825214, located in the T-box 5  DNA was extracted from peripheral blood samples using the Wizard Genomic DNA Purification Kit (Promega). Genotypes with rs3825214 were determined via a polymerase chain reaction (PCR)-based high-resolution melting system with LC Green Plus fluorescent dye  5′-AGGGCTAACACCACCAGT-3′; reverse, 5′-AATGAGTCTGTGTTGAGGTTTA-3′). A total of 25 µL of PCR mixture was prepared, containing 1 µL of LC Green dye, 0.5 µL of 5 pmol of each primer, 25 ng of genomic DNA template, 2.5 µL of 10×PCR buffer, 0.5 µL of 5 mmol DNTPs, and one unit of DNA Taq polymerase. PCR was then performed at 95°C for 5 minutes; followed by 40 cycles of denaturation at 95°C for 10 seconds, annealing at 56°C for 10 seconds, and elongation at 72°C for 15 seconds; and finally 72°C for 7 minutes.Primer pairs were designed based on the sequence of rs3825214 . To validate the accuracy of genotyping, 50 samples (randomly selected) were used to directly sequence the region of rs3825214 using BigDye Terminator v3.1 Cycle Sequencing Kits on an ABI PRISM3100 Genetic Analyzer . The genotypes of sequenced samples were completely consistent with the high-resolution melting analysis.t-test and Pearson's chi-squared (χ2) test were used to analyze the differences in continuous traits  and categorical traits  between the case and control groups, implemented with SPSS v17.0 software (IBM). The Hardy-Weinberg equilibrium was tested in the control group using PLINK v1.07 genetic analysis software (http://pngu.mgh.harvard.edu/~purcell/plink/download.shtml). A linear regression model was then used to test whether rs3825214 was associated with ECG parameters . To test the association between rs3825214 and AF or VT, allelic analysis and genotypic analysis under three genetic models  were also applied. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using Pearson's χ2 test. When the case-control samples were divided into several subgroups, Breslow-Day tests were performed to analyze the homogeneity between ORs from each subgroup . The Mantel-Haenszel test was performed to adjust for confounders. Multivariate logistic analysis was used to adjust for covariates such as age, gender, hypertension, CAD, stroke, and T2DM. To correct the data for multiple testing, the permutation test and Bonferroni correction were applied. Empirical P-values were determined using the PLINK v1.05 program with 100,000 Monte-Carlo permutations. Corrected P-values (Pcor) were obtained using Bonferroni's correction according to the formula: Pcor = 1−(1−Pobs)n, where Pobs is the observed P-value, and n is the number of comparisons. Statistical power analysis was conducted with the program PS  P-value<0.05 was considered statistically significant.Student's We studied 692 AF patients, 235 VT patients, and 856 controls . The avec intervals), using the program PLINK for the AF, VT, and control groups (P = 0.057). Of note, we observed an association between rs3825214 and QTc (P = 0.047).In this study, we performed an association analysis between the presence of rs3825214 and four ECG parameters . Neither of the genders was associated with minor allele G of rs3825214. There was a significant association between the G allele and AF  and between the G allele and AVB  even after adjusting for age, gender, hypertension, CAD, stroke, and T2DM by logistic regression. A significant association between minor allele G of rs3825214 and lone AF was found , which also survived the Bonferroni correction, while analysis of the other AF(AF outside of lone AF) showed no significant association (P = 0.546). Stratified analysis using the Breslow-Day test showed heterogeneity as measured by OR in the two subgroups (P = 0.049). Hence, among AF cases, the preponderance of associations between minor allele frequencies and AF was due to lone AF. When considering all patients with VT, there was no significant association between this condition and other cardiovascular diseases.Comparisons of the minor allele frequencies of rs3825214 among the groups are summarized in P = 0.029 and 0.003, respectively). No significant association was observed between genotypes carrying rs3825214 and ECG parameters. A bar chart of genotype distributions shows that the genotype GG made up the smallest proportion among the three genotypes  and two types of arrhythmias (AF and VT) in a Chinese Han population. Consistent with previous studies c, and conferred risk of lone AF in Han Chinese.In the present study, we assessed the association of rs3825214 with four ECG parameters , and AF, but not with the PR interval (P = 0.113).In an earlier study, the investigators were able to derive a predictor of postoperative AF or atrial flutter by measuring total P wave duration obtained from the simultaneous recording of the three standard limb leads P = 0.002). The association for GG frequencies of rs3825214 with lone AF is even more significant with the assumption of a dominant genetic model (P = 3.75×10−4) after adjusting for possible risk factors, including gender, age, T2DM, hypertension, and CAD.Lone AF patients are those with no detectable cardiovascular disease, about 30% of AF cases c  but not between rs3825214 and VT.The longer QT interval, which represents myocardial repolarization, is associated with a lowered ventricular arrhythmia threshold and is a risk factor for sudden cardiac death and drug-induced arrhythmias. In this study, the results also showed that rs3825214 was associated with QTTBX5 is important to heart and limb development. Mutation of TBX5 is the main cause of Holt-Oram syndrome, a hereditary disease characterized by forelimb and cardiac congenital defects such as atrial and ventricular septal defect TBX5 is required for the patterning and maturation of the murine cardiac conduction system and is widely expressed in the atrioventricular node and ventricular bundle branches in mice TBX5 may affect the development of paroxysmal AF, based on the research of a large atypical Holt-Oram syndrome family TBX5 may affect the cardiac conduction system and is involved in the pathogenesis of AF.As a member of the T-box transcription factor family, Our study has several limitations. (1) Although an association between rs3825214 and lone AF is demonstrated for the first time, the power to detect an association was only 60%, with an OR of 0.73 with a type I error probability of 0.05. Further studies with larger sample sizes are needed to further assess the association. (2) The diagnosis of lone AF needs to exclude more carefully other diseases that could initially present as lone AF. Though we set strict inclusion criteria for lone AF patients when using the GeneID database, many of the recorded lone AF cases are linked to other factors that are not well known TBX5 is associated with lone AF and prolonged QTc in a Chinese Han population.In conclusion, the present study was the first to provide evidence that rs3825214 in


RASSF1A) is one of the tumor suppressor genes (TSG). Inactivation of RASSF1A is critical to the pathogenesis of cancer. Aberrant TSG methylation was considered an important epigenetic silencing mechanism in the progression of ovarian cancer. A number of studies have discussed association between RASSF1A promoter methylation and ovarian cancer. However, they were mostly based on a small number of samples and showed inconsist results, Therefore, we conducted a meta-analysis to better identify the association.The RAS association domain family protein 1a gene  from individual studies using a fixed-effects model. We performed heterogeneity and publication bias analysis simultaneously.RASSF1A promoter methylation ranged from 30% to 58% (median is 48%) in the cancer group and 0 to 21% (median is 0) in the control group. The frequencies of RASSF1A promoter methylation in the cancer group were significantly higher than those in the control group. The pooled odds ratio was 11.17 (95% CI = 7.51–16.61) in the cancer group versus the corresponding control group under the fixed-effects model.Thirteen studies, with 763 ovarian cancer patients and 438 controls were included in the meta-analysis. The frequencies of RASSF1A promoter methylation had a strong association with ovarian cancer.The results suggested that  Ovarian cancer is the fifth most common cause of cancer deaths in women and accounts for the highest tumor-related mortality of gynecologic malignancies. Approximately 1.5% of females suffer ovarian from cancer and most cases are diagnosed at late stage owing to the lack of effective early detection methods TSG) promoter can lead to gene inactivation, which is critical to the pathogenesis of cancers, and occurs always in the early stage of cancer development in many types of cancer including ovarian cancer TSG was detected in tumor tissue and was associated with clinical features RASSF1A) is a putative tumor suppressor gene located on 3 p21 spanning 11,000 bp, containing eight exons and two different promoters RASSF1A promoter may play an important role in the development of ovarian cancer.Hypermethylation of the tumor suppressor gene . The similar search strategy was used in other databases. The search was limited to human studies, without language restrictions. A study included in the meta-analysis had to meet the following criteria: 1) studies which evaluated the association of RASSF1A methylation with ovarian cancer, 2) a case-control study or one including case and control populations, 3) a study reporting the RASSF1A methylation frequency in case and control groups, 4) sample type limited to tissues. First, the title and abstract of studies from the initial search were evaluated according to the inclusion criteria. Then all potentially relevant studies were evaluated as full-text papers. If a study was published more than once, only the most complete and up-to-date information was included in the meta-analysis. Online electronic databases ) were searched for published studies up to June 1, 2013. The following search strategy was performed in PubMed: (ovarian OR ovary) AND (cancer OR carcinoma OR tumor) AND  as prescribed by the Cochrane Handbook for systematic reviews.Three reviewers  independently reviewed the selected studies. The following information was extracted from these studies: first author’s name, year of publication, study population, sample size, age of women in the case group, control type, the status of the individuals in the control group, the number of individuals in the case and control groups, the measuring methods of methylation, and modulation frequencies of http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). The NOS has a maximum of nine ‘stars’ on items related to the selection of the study groups (four stars), the comparability of the groups (two stars) and the ascertainment of the outcome of interest (three stars). The studies were independently evaluated based on NOS by three reviewers . Studies with quality scores greater than or equal to 5 were included.The quality of those studies was evaluated according to the Newcastle Ottawa Scale (NOS) (RASSF1A methylation and ovarian cancer the pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. The x2-based Cochran Q statistic test and I2 statistics were used to test the heterogeneity among the included studies I2 was greater than 50%. When P<0.05 for the Q statistic, the heterogeneity was considered significant and a random-effects model (the DerSimonian-Laird estimate) was used to calculate the pooled ORs. Otherwise, a fixed-effects model (the Mantel-Haenszel method) was applied. A meta-regression (restricted maximum-likelihood estimator method) was employed to explore the source of heterogeneity. Furthermore, a subgroup analysis was performed to evaluate the source of heterogeneity. The contribution of each study to the final results of the meta-analysis was evaluated according to sensitivity analysis. We also used the Peters test, the Begg’s rank correlation method p values were two sides with a significant level at 0.05. When the individual studies have cells with zero counts, the default is to add 0.5 to all zero counts in the Meta package. All statistical analyses were performed with the Meta package http://www.r-project.org/).To assess the strength of the association between RASSF1A methylation data were excluded from full-text review. The studies were published between 2001 and 2012, and covered from 20 to 110 cases. Finally, 13 studies were included in our meta- analysis. Eight studies were of Asian subjects and five studies were of Caucasian subjects. Six studies analyzed methylation of RASSF1A promoter CpG islands RASSF1A promoter methylation RASSF1A methylation in ovarian cancer and control. Characteristics of the 13 studies are presented in A total of thirteen studies with 763 cases and 438 controls was included in the meta-analysis. 115 studies were initially identified by searching the electronic databases. 84 potentially relevant studies were retrieved for further evaluation after removing 31 duplicated articles. Based on their titles and abstracts, 61 studies were excluded . Four studies without a control group and six studies without The results of the NOS showed that most studies had a hospital control except for Li x2-based Cochran Q statistic test and I2 statistics did not detect a significant heterogeneity among the included studies . Then, we used a fixed-effects model to assess the association between RASSF1A promoter methylation and ovarian cancer. In the meta-analysis, RASSF1A promoter methylation frequency was significantly associated with ovarian cancer  (The 1–16.61) .Although tests did not find a significant heterogeneity across the studies, we first conducted meta-regression to explore potential sources of heterogeneity. Based on previous studies we assumed that heterogeneity may come from the population subgroup, sample size and control sample type. We conducted a multiple regression model with three variables . In the end, no source of significant heterogeneity was found . We perfRASSF1A promoter methylation and ovarian cancer was 14.76 (95% CI = 5.73–38.01) in Asians and 6.85 (95% CI = 3.46–13.58) in Caucasians under the fixed-effects model. Similarly, the OR for the case sample size subgroup was 8.93 (95% CI = 4.43–18.42) in the <50 case group under the fixed-effects model, and 11.19 (95% CI = 4.83–25.96) in the ≥50 case group under the random-effects model. In the subgroup analysis of control type, the OR was 8.43 (95% CI = 4.03–17.63) in the BAT group including benign ovarian tissues and adjacent tissues under the random-effects model and 16.50 (95% CI = 6.82–39.88) in the NT group under the fixed-effects model  to 12.99 (95% CI = 8.40–20.08) by omitting a single study under the random-effect model . No singP = 0.48) and the Begg’s rank correlation also did not detect publication bias (P = 0.14). The fail-safe number  also suggested that the study had a very small degree of publication bias.The study by Peters RASSF1A modulates multiple apoptotic, tubulin dynamics and cell cycle checkpoint pathways. Some studies found that the overexpression of RASSF1A promotes apoptosis and cell cycle arrest in cancer cell lines RASSF1A can be inactivated by gene mutation and promoter methylation and the latter accounted for the vast majority of cases RASSF1A promoter methylation is one of the most frequent epigenetic inactivation events detected in human cancer and leads to silencing of RASSF1A expression RASSF1A expression has been reported in lung, breast, bladder, gastric, cholangiocarcinoma and oesophageal sqaumous cell carcinoma primary tumors RASSF1A methylation level of the cancer group was significantly higher than the control group. The pooled odds ratio under fixed-effect model was 11.17 (95% CI = 7.51–16.61) in the cancer cases versus the controls. The result demonstrated that RASSF1A promoter methylation was associated with ovarian cancer, which was consistent with previous studies The present meta-analysis included thirteen articles with 763 cases and 438 controls. The RASSF1A promoter methylation and ovarian cancer in Asians was stronger than that in Caucasians. Similarly,Fraser’s study observed divergence of DNA methylation between African and European population, which may be due to methylation-associated SNPs (mSNPs) and complex epistasis or gene × environment interactions The summary OR was 14.76 (95% CI = 5.73–38.01) in Asians and 6.85 (95% CI = 3.46–13.58) in Caucasians. The association between RASSF1A promoter methylation between the case group and the NT group was greater than that between the case group and the BAT group. The result indicated that benign ovarian tissues and adjacent tissues had a higher frequency of RASSF1A promoter methylation than normal ovarian tissue, which also suggested that RASSF1A promoter methylation may play an important role in the pathogenesis of ovarian carcinoma For sample size, the summary OR was 8.93 (95% CI = 4.43–18.42) in the <50 case group and 11.19 (95% CI = 4.83–25.96) in the ≥50 case group. In another subgroup the summary OR changed a little between <50 case group and ≥50 case group. The ORs for the different control subgroup were 8.43 (95% CI = 4.03–17.63) for the BAT group and 16.50 (95% CI = 6.82–39.88) for the NT group. This result showed that the difference in frequency of There were some limitations in the study. The first limitation is potential confounder. Because there was a lack of information about variables in the control group, we only considered three variables  in the subgroup analysis. Another possible confounding factors could exist in the meta-analysis. The second limitation is publication bias. Although no significant publication bias was found according to the Peter’s test, negative and unpublished studies may lead to some bias.RASSF1A promoter was found to be associated with ovarian cancer according to the meta-analysis, which suggested that the promoter methylation of RASSF1A is a potentially useful biomarker in the carcinogenic process of ovarian cancer. The present study requires confirmation through well-designed prospective studies.In conclusion, hypermethylation of Checklist S1PRISMA Checklist.(DOCX)Click here for additional data file.


In this era of chronic diseases, large studies are essential in investigating genes, environment, and gene–environment interactions as disease causes, particularly when associations are important but not strong. Moreover, to allow expansion and generalization of the results, studies should be conducted in populations outside Western countries. Here, we briefly describe the Asia Cohort Consortium (ACC), a collaborative cancer cohort research project that was first proposed in 2004 and now involves more than 1 million healthy individuals across Asia. There are approximately 50 active members from Bangladesh, China, India, Japan, Korea, Malaysia, Singapore, Taiwan, Thailand, the United States, and elsewhere. To date, the work of the ACC includes 3 articles published in 2011 on the roles of body mass index, tobacco smoking, and alcohol consumption in mortality, diabetes, and cancer of the small intestine. Many challenges remain, including data harmonization, resolution of ethical and legal issues, establishment of protocols for biologic samples and transfer agreements, and funding procurement. Thus, the findings may not apply to other populations and the resulting genomic medicine might benefit only the few. Hence, a wider spectrum of populations should be investigated.4Prospective cohort studies provide the best level of observational evidence on disease causation. Furthermore, prospective cohort studies have specific strengths over clinical trials, which are often regarded as more powerful than observational studies in the hierarchy of evidence. For instance, in situations where it is unethical to design an experimental study , observational studies are the only way to undertake research. Further, unlike clinical trials, cohort studies can assess multiple outcomes for any 1 exposure or multiple exposures for a specific outcome. Chronic diseases are on the rise worldwide, and Asian countries face a growing disease burden and the many important health challenges that result.5 Moreover, a sufficiently large cohort or a population laboratory is essential for understanding the roles of genetic variation, environmental exposures, and the interaction between genes and exposures in the development of a disease.6 Analyses of gene–environment interactions in complex diseases with small interaction odds ratios or of genome–environment-wide interactions require even larger sample sizes to confirm associations.7,8 Potter has suggested that a cohort of at least 1 000 000 ethnically diverse individuals (“the Last Cohort”) is essential to discover disease susceptibility, early-detection biomarkers, and more-precise phenotypes.9Since the completion of the Human Genome Project, epidemiologic studies encompassing genetics have prospered, and the importance of prospective cohorts has been more widely recognized.10,11 Consortia are being established in and across many nations and research groups in order to produce expedited results and better understand the extent of international ethnic variation.10,12 One example is the Cohort Consortium of the National Cancer Institute (NCI), a collaboration of 43 high-quality cohorts consisting of more than 4 million people.13 The Cohort Consortium includes 4 signature initiatives that are actively producing valuable results: the Body Mass Index (BMI) and All Cause Mortality Pooling Project; the Breast and Prostate Cancer Cohort Consortium (BPC3); the Pancreatic Cancer Cohort Consortium; and the Vitamin D Pooling Project (VDPP). Through such collaborations, the complex process of identifying disease causes in relation to various genetic determining factors can be approached systematically.Combining existing cohorts is a strategy to achieve the desired results more quickly, more cheaply, and with similar scientific validity.14,15 The ACC was first proposed in November 2004 at a meeting in Seoul, Korea, and nearly all researchers at the meeting agreed on the need to establish a large consortium of cohorts. By establishing a cohort of at least 1 million healthy individuals around the world who will be followed until various disease endpoints, the ACC seeks to identify associations of diseases with genetics, environmental exposures, and their interaction, and to discover early-detection biomarkers.16 The ACC aims “(i) to serve as a platform for cross-cohort collaborative projects and combined analysis and (ii) to act as an incubator for new cohorts.” Led by co-chairs John Potter of the Fred Hutchinson Research Center, USA and Daehee Kang, Department of Preventive Medicine, Seoul National University College of Medicine, Korea, the ACC investigators meet biannually to update progress on existing and new cohorts in each country, to share ideas on data harmonization and development of common protocols, and to prepare collaborative projects. The ACC Coordinating Center (ACC CC) is located at the Fred Hutchinson Cancer Research Center and offers support for scientific collaboration, operations management, statistical and data management, and communications infrastructure and tool development. The activities of the ACC CC are described in detail elsewhere.14The Asia Cohort Consortium (ACC) is another large consortium of cohort-based studies in Pacific Rim countries, with approximately 50 active members from China, India, Bangladesh, Japan, Korea, Malaysia, Singapore, Taiwan, Thailand, the United States, and elsewhere Table .14,15 ThThe second meeting of the ACC was held in April 2005 at the Fred Hutchinson Cancer Research Center. At that meeting, the Steering Committee was established, consisting of principal investigators from various cohort studies in each participating country. To address and resolve the issues of standardization and harmonization across different cohort studies, Working Groups were established in the areas of diet and nutrition, obesity and physical activity, occupation and environment, alcohol and tobacco use, family history and genetics, biospecimens and sample collection, data collection and management, and follow-up and endpoint ascertainment. Currently, consortium members are collaborating on projects examining: body mass index (BMI) and various outcomes; rare cancers, including cancers of the small intestine and pancreas, which are infrequent and thus difficult to study in single studies; and biospecimen use across existing Asian cohorts.Proposals initiating a collaborative project can be submitted throughout the year. Before every biannual meeting, all proposals are reviewed by the Executive Committee (EC) and ACC members. Proposals from anyone interested in collaborating with the ACC are also reviewed, including those from non-ACC scientists who are sponsored by an ACC member. Data analysis and project coordination are performed by the Coordinating Center at the Fred Hutchinson Cancer Research Center.ACC participants are self-funded, and individual projects usually require a grant proposal to secure funding. The ACC has 2 funded grant proposals from the US NCI on rare cancers and BMI and on BMI and mortality, as well as other projects under review. Larger grant proposals are currently being drafted.17–19 The first article published by the group was a pooled analysis of BMI and risk of death among more than 1.1 million persons from 19 cohorts in Asia.17 We reported a U-shaped association between BMI and mortality in East Asians that subtly differed from the associations observed in studies of North American and European populations. These observations were possible largely because, in Asia, we were able to study the association between very low BMI and mortality, an opportunity that has not existed in populations of European origin for many decades. A U-shaped association was also reported in a 2011 pooled analysis of 7 large-scale cohort studies in Japan.20 In contrast, among Indians and Bangladeshis, there was no elevated risk of death in high BMI groups. These results provide important new public health data, as few previous studies have been conducted on BMI and overall risk of death in Asian populations, which account for more than 60% of the world’s population. The second article was a pooled cross-sectional analysis of BMI and self-reported diabetes that included more than 900 000 individuals from 18 cohorts.18 As was the case for BMI and mortality, the overall impact of BMI on diabetes risk had not been adequately studied in an Asian population. This study encompassed 7 Asian countries and established the shape and strength of the association between BMI and diabetes. Similar to the previous results, a positive association between BMI and diabetes prevalence was shown in all analyzed cohorts and all subgroups of the study population. The third, and most recent article, published by the ACC reported the findings of a study of the association of cancer of small intestine with BMI, tobacco smoking, and alcohol drinking, using a pooled analysis of over 500 000 individuals from 12 cohorts.19 The analysis of 134 incident cases showed a trend toward an increased hazard ratio of 1.50  in the high BMI (BMI >27.5 kg/m2) group. Although the results were not statistically significant, they support the hypothesis that elevated BMI is a risk factor for cancer of the small intestine. No association was observed for tobacco smoking or alcohol drinking.The first cross-cohort collaborative project, BMI in Asian populations, has yielded 3 articles to date Table .17–19 Th21,22 Furthermore, standardizing and harmonizing new and continuing cohorts, and incorporating them into the existing study in a valid way, is similarly complex and time-consuming. Phenotypic measures, specific measurement tools, and other areas may be discordant across studies.11 Biospecimens present unique challenges. The quality of samples collected and stored under different protocols and for varying periods may differ among cohorts. Sample transfer between countries is sometimes a problem. Ethical and legal issues regarding informed consent of study participants and the use of their information for international studies are other areas that need to be resolved. To fulfill the collective enthusiasm and talent of workers in the ACC, funding is a constant necessity. We have begun well, but there is a great deal left to do.Many challenges remain for the ACC. The first is harmonizing data from legacy cohorts. For instance, some questions on exposures were asked differently and demand more careful standardization. Even more complex is the need for new infrastructure, such as the establishment of an Asian nutrient database. Much work is left to be done in the field of nutrition, especially when using data from multiple countries.


GSTM1, GSTT1, and GSTO2) in relation to the work place contribute to the development of cataract.To investigate whether genetic polymorphisms of glutathione S-transferases  based methods.The present case-control study consisted of 186 patients  with cataract and 195 gender-matched healthy controls  were randomly selected from unrelated volunteers in the same clinic. The GSTM1 increased the risk of cataract . The prevalence of GSTT1 and GSTO2 genotypes was similar between cases and controls. There was significant difference between cases and controls for work place . Genetic polymorphisms  and work place that were significant by p<0.3 in the univariate analysis were included in the analysis for investigating the additive effects of the genotypes and work place on risk of cataract. Statistical analysis showed that the risk of cataract increased as a function of number of putative high risk factors .The null genotype of GSTM1 and GSTO2 and also work place may act additively for developing cataract.This finding suggests that the polymorphisms of  EC 2.5.1.18) are a superfamily of ubiquitous multifunctional cytosolic soluble detoxification enzymes that can catalyze the conjugation of reduced glutathione to various xenobiotics and endobiotics [GSTM1 , GSTT1 , and GSTO2  have been defined [GSTM1–0 (GSTM1 null) and GSTT1–0 (GSTT1 null) alleles represent deletions of GSTM1 and GSTT1 genes, respectively. The functional consequences of homozygosity for the GSTM1 and GSTT1 null alleles (null genotypes) are obvious in terms of enzyme activity: no gene, no enzyme, and no activity [GSTM1, GSTT1) and risk of cataract have been studied [GSTM1 and GSTT1 null genotypes are both associated with increased risk for senile cataract in Asian populations but not in Caucasian populations [Cataract is a multifactorial disease which is associated with many environmental  and geneobiotics -9. GSTs  defined -9. The Gactivity ,8. The h studied -12. BaseGSTO2 have poor activity with common GST substrates, but exhibit novel glutathione-dependent thioltransferase, dehydroascorbate reductase, and monomethylarsonate reductase activities [GSTO2 is polymorphic with an N142D substitution in the coding region [2O3 inhibits the growth and induces apoptosis of cultured human lens epithelium cells [GSTO2 N142D polymorphism may have an effect on individual susceptibility to many multifactorial diseases, such as cataract.The tivities . In humag region . It is rg region . It is sum cells . Taken tThere is no study investigating the additive effects of these polymorphisms in relation to work place (as an indicator for exposure to sunlight) and the cataract risk. To get more insight into the possibility of contribution of these genetic variations to susceptibility of senile cataract, the present study was performed.Patients with senile cataract were recruited from Khalili Hospital Ophthalmic Clinic in Shiraz, Iran. All 186 subjects with cataract had severe visual disturbance and their corrected visual acuities were under 0.1. We excluded patients with secondary cataract due to diabetes, trauma, steroid administration, and other causes. The gender-matched control subjects were collected from unrelated volunteers in the same clinic. Iranian population is one of the most heterogeneous populations ,17. TherInformed consent was obtained from each subject before the study. This study was approved by the local ethics committee. Informed consent was obtained from all participants.The study subjects were divided into two groups: outdoor  and indoor  according to their job titles. The outdoor and indoor patients were occupationally exposed to sunlight and not exposed to sunlight, respectively.GSTM1, GSTT1 and GSTO2 genotypes were the same as those reported previously [Blood samples were obtained from patient and control groups. Immediately after collection, whole blood was stored at −20 °C until use. Immediately after blood collection, whole blood was stored at −20 °C until use. Genomic DNA for PCR was isolated from whole blood using the thawed blood samples . The prieviously  and show2 test was performed for GSTO2 polymorphism to determine if the control samples demonstrated Hardy–Weinberg equilibrium. Unconditional logistic regression was used to calculate ORs and 95% CI for cataract risk associated with the genetic polymorphisms of GSTs. Considering the significant age difference between patients and controls, in further analysis, logistic regression was used to calculate ORs and 95% CI for the various genotypes after adjusting for age. In these analyses the reference group consisted of putative low risk genotypes .A χGSTs polymorphisms, the “sensitivity analysis” was used [Data on work place in the control subjects were missed for some participants. To study the potential effect of the work place on cataract risk when investigated the risk associated with genotypes of was used . For doik Type I error rate, where α=0.05 and k is the number of comparisons made . However, this results in a very conservative estimate of the statistical significance of each evaluation.Statistical analysis was performed using the Statistical Package for Social Sciences . In multiple comparisons, the error rate is often much larger than the error rate applied to each single analysis. This can result in the declaration of spurious effects as significant. Bonferroni adjustment, requires that each analysis be performed using an α/GSTO2 N142D, GSTM1, and GSTT1 genetic polymorphisms in cataract patients and healthy controls. Control subjects for the genotypic frequencies of the GSTO2 polymorphism were in Hardy–Weinberg equilibrium . Logistic regression analysis showed that there was no significant association between GSTO2 polymorphism and susceptibility to cataract . The prevalence of GSTT1 null genotype was similar between cases and controls . It should be mentioned that work place was missing for 34 participants of controls.Patients and control subjects worked in outdoor, 25.8 and 16.7%, respectively. Work place significantly differed between cases and controls  and work place that were significant by p<0.2 in the univariate analysis were included in the analysis for investigating the additive effects of the genotypes and work place. GSTM1 and NN genotype of GSTO2 polymorphism).Genetic polymorphisms . Therefore the main finding of the present study which indicating that outdoor working, null genotype of GSTM1 and ND+DD genotype of GSTO2 act additively in relation to susceptibility to cataract. Previously, it has been reported that some polymorphisms have additive effect on risk of other diseases or multifactorial traits [To show the additive effect(s) of  factors . The res factors . There wl traits -24.GSTM1 and GSTO2 and work place are associated additively with increased risk for senile cataract in an Iranian population. Considering that the GSTM1 and GSTT1 null genotypes are both associated with increased risk for senile cataract in Asian populations but not in Caucasian populations [In summary, the present study suggested that polymorphisms of ulations , more epOne of the main limitations of the present study is the measurement of sunlight exposure as a dichotomous variable (indoor versus outdoor). In future, our findings should be confirmed by a large-scale study. It is recommended that in future studies, sunlight exposure is measured as a variable with more categories or as a continuous variable. Difference between cases and controls for age of subjects is another limitation of our study.


CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus.Two variants in the gene encoding the cytochrome P450 2C9 enzyme  and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses.We conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation.Our data show no significant difference in the frequency of  There are genetic variations in genes encoding for the hepatic CYP450 metabolizing enzymes that can lead to undesirable drug reactions or inadequate response to commonly prescribed doses, either because of reduced or enhanced enzyme activity, respectively . Testinghttp://www.fda.gov/). Candidate-gene association studies have identified two genes responsible for the main proportion of warfarin response: CYP2C9, which codes for the enzyme cytochrome CYP450 2C9 that metabolizes S-warfarin [VKORC1, which codes for warfarin’s target, vitamin K epoxide reductase [CYP2C9*2 (Arg 144 to Cys) and CYP2C9*3 (Ile 359 to Leu) are recognized as the main CYP2C9 variants in humans, affecting negatively the enzyme activity [CYP2C9 and VKORC1 genetic profile seem to predict pretty accurately the required warfarin dose for each patient [It is notable that in August 2007, the FDA label for warfarin, a frequently used anti-coagulant drug, was updated to highlight the benefit of genetic testing to predict warfarin response. This was renewed on February 2010 , so that upon amplification a restriction recognition site for Comparison of population allele frequencies was performed through Pearson chi-square test, using SPSSv.15 statistical package . The significance level, alpha, was set to 0.05. Hardy-Weinberg equilibrium was tested for all the analyzed polymorphisms through an Excel based application (Microsoft Office 2007).CYP3A5*3 allele (no homozygous wild-type CYP3A5*1/*1 were found), which is responsible for reduced tacrolimus clearance, while 88.5% of them are homozygous CYP3A5*3/*3  activity (*1/*1 > *1/*2 > *1/*3 > *2/*2 > *2/*3 > *3/*3). The effect of the CYP2C9*3/*3 genotype is the most severe one with clearance of S-warfarin being 10% of the wild type genotype [VKORC1 encoded enzyme interacts with warfarin, so the enzyme levels can affect sensitivity to warfarin. Jorgensen et al. [CYP2C9*3 and VKORC1 variants are significant for warfarin dose determination for most ethnic populations [It has been proven that genotype . VKORC1 n et al. , revieweulations . Sconce ulations  showed culations .VKORC1-1639A allele (Table In conclusion, it is evident through population specific studies, like the one we present here, that pharmacogenetics allele frequencies can differ significantly in different sub-populations. The results of our study compare well to those of other Caucasian populations, but with some notable differences, like the increased frequency of the The authors declare that they have no competing interests.VKORC1 variant. All authors read and approved the final manuscript.CD and KV conceptualized the study, collected the samples, supervised genotyping and wrote the manuscript. KV performed the statistical analysis. DH performed most of the genotyping of this study and she categorized the data. SC genotyped the


The associations, derived from sporadic, inconsistent, small-sample-size studies, need to be evaluated further in a meta-analysis.Relevant studies were identified by searching PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Eligible data were extracted from each included study. Odds ratios (ORs) were calculated using a fixed-effects or a random-effects model. The ORs and 95% confidence interval (CI) were used to assess the strength of the association between serotonergic gene polymorphisms and OSAS in the dominant and recessive models, as well as alleles. The Q statistic was used to evaluate homogeneity and Begg’s test was used to assess publication bias.Eight studies were finally included in the meta-analysis of the association between 5-HTR2A gene variants (including 102T/C and 1438G/A), 5-HTT gene polymorphisms (including 5-HTT gene-linked promoter region (5-HTTLRP), and serotonin transporter intron 2 variable number tandem repeat (STin2VNTR) and OSAS risk. The G allele of 5-HTR2A 1438G/A, long 5-HTTLPR, and 10-tandem-repeats STin2VNTR were shown to increase OSAS susceptibility, with ORs of 2.33 , 1.24 , and 2.87 , respectively. These significant differences were determined in both dominant and recessive models. Of the 5-HTR2A 1438G/A gene polymorphism, the AA genotype increased the OSAS risk, with an OR of 4.21 (95% CI: 2.83–6.25) in a recessive model in male OSAS patients, but no significant association was found in females.Our meta-analysis demonstrated that polymorphisms in the 5-HTR2A 1438G/A and 5-HTT genes contributed to susceptibility to OSAS. The A allele of the 1438G/A gene polymorphism is predominantly distributed in males and increased the OSAS risk significantly. Because of its high morbidity and mortality, obstructive sleep apnea syndrome (OSAS) has recently become an important public health issue. It affects about 2% of females and 4% of males in middle-aged groups in Western counties Serotonergic neurons innervating motoneurons increase their firing rates in response to respiratory challenges, and long-term facilitation of respiratory activity in response to hypoxia is 5-hydroxytryptamine -dependent There is a large family of 5-HT receptors The 5-HT transporter  gene is located in the 17q11.1–17q12 region of chromosome 17 Although the various studies have provided important serotonergic genetic information regarding susceptibility to OSAS This study was strictly followed the guidelines of the PRISMA .To identify all eligible studies that address the association between 5-HT receptor and transporter gene polymorphisms and OSAS, we conducted key word searches in the biomedical electronic databases, including PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu: (obstructive sleep apnea hypopnea syndrome or OSAHS or obstructive sleep apnea syndrome or OSAS or obstructive sleep apnea or OSA or sleep apnea or apnea) and (5-hydroxytryptamine receptor or 5-HTR or serotonin receptor or 5-hydroxytryptamine transporter or 5-HTT or serotonin transporter) in combination with  were used as research terms. The final search was updated in June 2013. The search was limited to studies published in English and Chinese.Case-control studies that met the following criteria were included: 1) published in peer-reviewed journals, 2) contained independent data, 3) had enough data to evaluate the relationship between gene polymorphisms and OSAS susceptibility, and 4) had enough data to determine the genotype distributions in both the case and control groups. The authors were contacted if there were queries regarding the studies.Studies were excluded for the following reasons: 1) lack of a suitable control group, 2) no usable data reported, 3) data were contradictory, 4) repeated data, and 5) abstracts or reviews.Two investigators (Drs. Xu and Guan) performed the data search, data screening, and data extraction independently. Disagreements regarding data screening and extraction were resolved by discussion. If there was still disagreement, a third reviewer (Prof. Yin) participated to resolve the issue. The following data were extracted from the original studies: first author, year of publication, country, sample size, age, gender, body mass index (BMI), apnea-hypopnea index (AHI), and genotype frequency.The Review Manager software , the SAS software , and Stata  were used for the meta-analysis and statistical analyses. For genetic frequency distributions, Hardy-Weinberg equilibrium (HWE) was calculated with the SAS software to assess goodness of fit. Homogeneity was tested using Cochran chi-squared tests. The Mantel-Haenszel fixed-effects model or the random-effects model was used for the meta-analysis in the comparison of serotonergic gene polymorphisms In total, 52 studies were identified by electronic and manual searching. At the stage of screening by the inclusion criteria, 38 studies were excluded for the following reasons: animal studies, cell studies, reviews, or not correlated with OSAS. At the stage of screening by the exclusion criteria, after reading the full articles, six studies were excluded for the following reasons: two articles were repeated studies 2 to 29.3±3.7 kg/m2, although one study lacked these data All eligible studies were published between 2005 and 2013. Five studies were from China The allele frequencies of all OSAS and control samples were in HWE except one study . The comThe association between gene polymorphisms and susceptibility to OSAS was evaluated in the total case and control populations combined from eligible studies of each gene locus. All genetic loci were tested in a dominant model, a recessive model, and a susceptibility allele versus insusceptibility allele model.2 of the dominant models (TT+TC vs. CC), recessive model (TT vs. TC+CC) and T allele vs. C allele were 0 and the p values of the Q test were higher than 0.1, suggesting no significant heterogeneity among the studies, so we used a fixed-effects model to analyze the data. As shown in Of the 5-HTR2A 102T/C polymorphisms, six studies containing 566 case subjects and 728 controls were included in this meta-analysis 2 of the dominant models (AA+AG vs. GG) and the A allele vs. G allele were over 50%, and the p values of the Q test were 0.47 and <0.01, respectively, suggesting strong heterogeneity among the studies. So, these data were analyzed using a random-effects model. The meta-analysis revealed that the A allele was associated with OSAS risk with an OR of 2.44 (95% CI: 1.11–5.38) in the dominant model (AA+AG vs. GG). The A allele increased the OSAS risk with an OR of 2.33 (95% CI: 1.48–3.66) compared with the G allele (2 of the recessive model (AA vs. AG+GG) was 0 and the p value of the Q test was less than 0.01, so we used a fixed-effects model to analyze the data. As shown in For the 5-HTR2A 1438G/A polymorphism, five studies had 466 case subjects and 551 controls G allele . The I2 2 of the dominant model (LL+SL vs. SS), recessive model (LL vs. SL+SS), and L allele vs. S allele were 0 and p values of the Q test were all more than 0.1. Meta-analysis with a fixed-effects model showed that the LL genotype increased the OSAS risk at an OR of 1.52 (95% CI: 1.07–2.16) when compared with a population with LS or SS genotypes. A single allele L increased the OSAS risk at an OR of 1.24 (95% CI: 1.04–1.49) compared with the allele S  and recessive model (10/10 vs. 10/12+12/12), were 5 and 0, and the p values of the Q test were 0.35 and 0.72, respectively. Meta-analysis using a fixed-effects model showed that 10 tandem repeats increased the OSAS risk with an OR of 2.13 (95% CI: 1.53–2.96) and 4.10 (95% CI: 1.48–11.35) in a dominant model (10/10+10/12 vs. 12/12) and recessive model (10/10 vs. 10/12+12/12), respectively . For gender, two Begg’s test was used to evaluate publication bias in the literature. The shapes of the funnel plots revealed no obvious asymmetry (not shown). We then used Begg’s test to assess statistical evidence of funnel plot symmetry, but no significant publication bias was indicated .Although the genetic basis of OSAS is poorly understood, studies to date have focused on relationships between gene polymorphisms and susceptibility to OSAS Although race is a major factor in the distribution of gene polymorphisms, and our study data were from Japan During the preparation of this manuscript, a systematic review and meta-analysis of the association between 5-HT2A receptor polymorphisms and risk of OSAS was published 5-HT is associated with circadian rhythm and breathing regulation, and the 5-HTR2A and 5-HTR2C subtypes play an important role in the maintenance of upper airway stability and normal breathing in obesity This meta-analysis had a number of limitations. First, the pooled subjects in our meta-analysis were relatively small. Second, some studies with negative results may not have been reported, which will likely increase the publication bias in a meta-analysis. Despite these limitations, meta-analysis is a cost-effective and reasonable approach to evaluating sporadic, inconsistent, and small-sample-size studies.In conclusion, we demonstrated by a meta-analysis that the 5-HTR2A 1438G/A, 5-HTTLPR, and STin2VNTR polymorphisms confer susceptibility to OSAS. The AA genotype increased the OSAS risk with an OR of 4.21 (95% CI: 2.83–6.25) in a recessive model in male OSAS patients, although no significant association was found in females. Further studies using larger samples, of better designs, and that include additional ethnicities are warranted. Additionally, the biological mechanism(s) and function(s) of the 5-HTR and 5-HTT genotypes and haplotypes in the pathogenesis of OSAS should be investigated further.Table S1Characteristics summary of publications included in meta-analysis.(XLS)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


Diabetes is associated with increased risk of cancer at several sites, but its association with risk of bladder cancer is still controversial. We examined this association by conducting a systematic review and meta-analysis of cohort studies.Studies were identified by searching PubMed, EMBASE, Scopus, Web of Science, Cochrane register, and Chinese National Knowledge Infrastructure (CNKI) databases through April 29, 2012. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model.2 = 84%). When restricting the analysis to studies that had adjusted for cigarette smoking (n = 6) or more than three confounders (n = 7), the RRs were 1.32 (95% CI 1.18–1.49) and 1.20 (95% CI 1.02–1.42), respectively. There was no significant publication bias (p = 0.62 for Egger’s regression asymmetry test).A total of fifteen cohort studies were included in this meta-analysis. Analysis of all studies showed that diabetes was associated with a borderline statistically significant increased risk of bladder cancer (RR 1.11, 95% CI 1.00–1.23; p<0.001 for heterogeneity; IOur findings support that diabetes was associated with an increased risk of bladder cancer. More future studies are warranted to get a better understanding of the association and to provide convincing evidence for clinical practice in bladder cancer prevention. Urinary bladder cancer ranks ninth in worldwide cancer incidence. It is the seventh most common malignancy in men and seventeenth in women Over the past few decades, the prevalence of diabetes mellitus has increased substantially and is highly suspected to be associated with an increased risk of some cancers. Considerable epidemiological studies and systematic reviews have shown positive associations between diabetes mellitus and the risk of biliary tract cancer A meta-analysis of the association between diabetes and bladder cancer risk published in 2006 concluded that diabetes was significantly associated with a higher risk (24%) of bladder cancer Given the inconsistency of the existing literature and the insufficient statistical power of primary studies, we performed a meta-analysis of all eligible cohort studies to derive a more precise estimation of the relationship between diabetes and risk of bladder cancer. Furthermore, we also examined whether the association between them differs according to various study characteristics.We carried out a search in PubMed, EMBASE, Scopus, Web of Science, Cochrane register, and Chinese National Knowledge Infrastructure (CNKI) databases, covering all the papers published from their inception to April 2012. The search strategy included terms for outcome (bladder neoplasm or bladder cancer or bladder tumor) and exposure (diabetes or diabetes mellitus). We evaluated potentially relevant publications by examining their titles and abstracts and all the studies matching the eligible criteria were retrieved. We also checked the references from retrieved articles and reviews to identify any additional relevant study.Studies included in this meta-analysis had to meet all the following criteria: (a) they had a cohort design or nested case-control design; (b) one of the exposure of interest was diabetes mellitus; (c) one of the outcome of interest was incidence of bladder cancer; and (d) studies provided rate ratio, hazard ratio or standardized incidence ratio (SIR) with their 95% CIs, or data to calculate them. Studies on mortality rates from bladder cancer were not included, as it could be confounded by survival related factors. We also did not consider studies in which the exposure of interest was mainly or solely type 1 diabetes, which was defined as early-onset (age <30 years) of diabetes. If multiple publications from the same study population were available, the most recent and detailed study was eligible for inclusion in the meta-analysis.Data were extracted independently by two authors using a predefined data collection form, with disagreements being resolved by consensus. For each study, the following characteristics were collected: first author’s name, year of publication, the country in which the study was carried out, participant characteristics (age and gender), year of study conducted, range for follow-up, sample size (cases and cohort size), methods of ascertainment of diabetes and bladder cancer, estimate effects with their 95% CIs, and covariates adjusted for in the analysis. From each study, we extracted the RR estimate that was adjusted for the greatest number of potential confounders.Studies that reported different measures of RR were included in this meta-analysis: rate ratio, hazard ratio and SIR. In practice, these three measures of effect yield similar estimates of RR because the absolute risk of bladder cancer is low.Summary RR estimates with their corresponding 95% CIs were calculated with the DerSimonian and Laird 2 score. Publication bias was assessed using Begg’s test (rank correlation method) Homogeneity of RRs across studies was tested by Q statistic (significance level at P<0.10) and the IAfter full-text review of 21 papers, 6 studies were excluded for the reasons as follows: overlapping publications from the same study population The characteristics of the 15 cohort studies are presented in 2 = 84.0%).The overall RR with its 95% CI showed a borderline statistically significant association between diabetes mellitus and risk of bladder cancer (2 = 0%) than in Europe  or USA . In further stratified analysis by the methods of ascertainment of diabetes, the summary RRs with 95% CIs were 1.34 (95% CI 1.11–1.62) for studies using self-report, and 1.11 (95% CI 0.95–1.31) for others methods.Next, we conducted subgroup meta-analysis by various study characteristics . In the 2 = 0%). Moreover, some studies in our analysis adjusted for more than three confounders. Therefore, we examined if more thoroughly adjusting for potential confounders affected the pooled RR and degree of heterogeneity (2 = 85.6%).We also investigated the impact of confounding factors on the estimates of relative risk . Cigaretogeneity . The effThere was no evidence of significant publication bias either with the Begg’s test (P = 0.76) or with Egger’s test (The findings of this meta-analysis of fifteen cohort studies indicate that diabetes is associated with an 11% increased risk of bladder cancer. It tended to be more remarkable for studies with a rate ratio or hazard ratio as the measure of relative risk than for studies with a standardized incidence ratio.At present, whether diabetes is independently associated with incidence of bladder cancer remains controversial. Results from our subgroup analysis restricted to studies with control for smoking or adjusted for more than three confounders were more robust than that reported in the overall analysis, which indicated that the association may have been diluted by poor study methodologies and diabetes is probably an independent risk factor of bladder cancer.Of note, the association between diabetes and bladder cancer was more pronounced in studies with a rate ratio or hazard ratio as the measure of relative risk than in studies with a standardized incidence ratio. Studies using standardized incidence ratio and standardized mortality ratio to estimate the relative risk may underestimate the true relative risk The association between the duration of diabetes and risk of bladder cancer have been assessed in some studies, and inconsistent results were found A relationship between diabetes and risk of bladder cancer is biologically plausible. Type 2 diabetes is associated with insulin resistance, compensatory hyper-insulinemia, and up-regulated level of IGF-1. IGF-1 could stimulate cell proliferation and inhibit apoptosis. Several epidemiological studies have implicated IGF-I in the development of breast and colorectal cancers Substantial heterogeneity was observed among studies of diabetes and bladder cancer risk, which may be due to different adjustment for confounding factors and different mixtures of type 1 and type 2 diabetic patients. Some studies included in this meta-analysis did not distinguish between type 1 and type 2 diabetes. As type-1 diabetes may not be related to bladder cancer risk A major strength of our study is that with the accumulating evidence and enlarged sample size, we have enhanced statistical power to derive a more precise and reliable estimation of the relationship between diabetes and bladder cancer risk. Nonetheless, some limitations should be mentioned. One potential limitation of this meta-analysis was the various assessments of diabetes used between studies. Some studies used self-report as the method of diabetes ascertainment, which may lead to some misclassification of diabetic persons as non-diabetic persons. This underreporting may result in an underestimate of the magnitude of the association between diabetes and bladder cancer risk. However, earlier studies have suggested that self-reported diabetes have good agreement with medical records In summary, our findings support that diabetes was associated with the increased risk of bladder cancer. More future studies are warranted to get a better understanding of the association and to provide convincing evidence for clinical practice in bladder cancer prevention.


TNF) gene has been implicated in the risk of acne vulgaris, but the results are inconclusive. The present meta-analysis aimed to investigate the overall association between the -308 G/A polymorphism and acne vulgaris risk.The -308 G/A polymorphism in the tumor necrosis factor . Subgroup analysis by ethnicity showed that the acne vulgaris risk associated with the -308 G/A gene polymorphism was significantly elevated among Caucasians under recessive model .A total of five publications involving 1553 subjects (728 acne vulgaris cases and 825 controls) were included in this meta-analysis. Combined analysis revealed a significant association between this polymorphism and acne vulgaris risk under recessive model (OR = 2.73, 95% CI: 1.37–5.44, TNF gene contributes to acne vulgaris risk, especially in Caucasian populations. Further studies among different ethnicity populations are needed to validate these findings.This meta-analysis suggests that the -308 G/A polymorphism in the  Acne vulgaris is a chronic inflammatory skin disease widely affecting adolescents and young adults TNF) gene transcripts was observed in acne lesions Inflammation plays one of the main roles in the development of acne vulgaris TNF gene promoter have been identified TNF expression. One of these polymorphisms at position -308 (TNF -308 G/A) had been reported associated with regulation of TNF expression by, e.g., interfering with transcription factor binding sites or other regulatory elements Several single nucleotide polymorphisms (SNPs) in the TNF gene and the risk of acne vulgaris TNF -308 G/A polymorphism and acne vulgaris risk based on all eligible case-control studies.A number of case-control studies were conducted to investigate the association of -308 G/A polymorphism in the TNF gene and acne vulgaris risk. A date limit of August 1, 2013 was applied. The search was performed without any restrictions on language. The search terms were as follows: “Acne vulgaris” or “Acne” in combination with “TNF” or “tumor necrosis factor”. The reference lists of identified studies and review articles were manually searched to find additional relevant publications.Two authors independently performed systematic searches in Pubmed, Embase, Web of Science and CNKI  databases to identify studies examining the association between the -308 G/A polymorphism in the TNF gene -308 G/A polymorphisms and acne vulgaris risk; (2) genotype frequencies were available for cases and controls; (3) the distribution of genotypes in the control group was consistent with Hardy-Weinberg equilibrium (HWE). (4) when publications involved the overlapping data sets, only the study with the largest number of participants was included. The supporting PRISMA checklist is available as Studies were included in the meta-analysis if they satisfied the following inclusion criteria: (1) case-control studies focused on associations between Two authors independently extracted data from the included studies. The following data were extracted: the name of the first author, year of publication, country of origin, ethnicity, sample size, genotyping method and genotype frequencies in acne vulgaris cases and controls. In case of conflicting evaluations, disagreements were resolved through discussion between the authors.TNF -308 G/A polymorphism and risk of acne vulgaris was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). The significance of the pooled OR was determined using the Z-test and p<0.05 was considered statistically significant. We estimated the association based on four genetic models: allele model (A vs. G), dominant model (AA + AG vs. GG), recessive model (AA vs. AG + GG) and additive model (AA vs. GG).The association between the χ2-based Q statistic and I2 test, with p<0.10 or 2I>50% considered statistically significant p≥0.10 or 2I≤50%, the pooled OR was calculated using a fixed effect model (Mantel-Haenszel method); otherwise, a random effect model (DerSimonian Laird method) was used.To evaluate whether the association showed any ethnicity-specific effects, we analyzed the data for separate subgroups defined by ethnicity. Heterogeneity was evaluated using a χ2 test was used to determine whether the observed frequencies of genotypes in control group conformed to the HWE Publication bias was assessed using Begg's funnel plots and Egger's test TNF -308 G/A polymorphism and acne vulgaris risk were included in the meta-analysis, involving 1553 subjects (728 acne vulgaris cases and 825 controls) The flow chart that displays the study selection process was shown in Q test and 2I test under the majority of genetic models (2I>50%), the analysis was conducted using random effect model. The meta-analysis results showed that TNF -308 G/A polymorphism was linked to the risk of acne vulgaris under recessive and additive models  (With significant between-study heterogeneity by ctively) . ResultsTNF -308 G/A polymorphism might significantly increase the risk of acne vulgaris among Caucasian populations . TNF -308 G/A polymorphism might show significant association with the increased risk of acne vulgaris in all genetic models among Asian populations , but not enough reliability was established due to the result from a single study In the subgroup analysis based on ethnicity, the results indicated that p>0.05).Sensitivity analysis were performed by sequential omission of individual studies for all subjects and subgroups. The corresponding pooled ORs were not significantly altered in all subjects and subgroups (data not shown). The results of sensitivity analysis indicated the stability of our results. Begg's funnel plot and Egger's test were used to assess publication bias. The shape of the funnel plots in all the genetic models seemed symmetrical, indicating that there were no evidences for obvious publication bias. Further, Egger's test provided similar results that there were no statistically significant publication bias in all genetic models  between HLA-B and DR within the class III region of the major histocompatibility complex TNF gene  −308. The polymorphism may affect cytokine production TNF -308 G/A polymorphism was associated with acne vulgaris risk. However, the conclusion was controversial. To the best of our knowledge, our article is the first meta-analysis evaluating the association between TNF -308 G/A polymorphism and acne vulgaris risk. We performed the present meta-analysis of eligible five independent case-control studies, including 728 cases and 825 controls. We were able to provide a more complete picture of the role of TNF -308 G/A polymorphisms in acne vulgaris risk, as comparing with that published in individual studies.The >When all the eligible studies were pooled into the meta-analysis, the results showed that -308 G/A polymorphism was associated with the risk of acne vulgaris under the recessive model, with AA homozygote at higher risk of acne vulgaris than AG heterozygote and GG homozygote. In addition, we performed a stratified analysis based on ethnicity. The results showed that -308 G/A polymorphism might increase the risk of acne vulgaris among Caucasian population under recessive model, and that the homozygotic AA genotype may be a risk factor for acne vulgaris. We also found the -308 G/A polymorphism to be a risk factor for acne vulgaris among Asians, but the result in Asian population was not reliable enough due to the estimation from a single study TNF -308 G/A polymorphism have been examined in several autoimmune and inflammatory diseases, such as psoriasis, lepromatous leprosy and systemic lupus erythematosus TNF -308 A allele had shown to be a stronger transcriptional activator than the common TNF -308 G allele in vitro and patients with TNF -308 GA heterozygosity had increased TNF production TNF -308 G/A polymorphism and acne vulgaris risk. Second, the included publications were limited to Caucasian and Asian populations, so future work should examine other populations. Third, although no obvious publication bias was identified, potential bias cannot be completely ruled out. Fourth, there had been some differences in severity of cases between the included studies Click here for additional data file.


Objectives: Genetic factors and environmental factors play a role in pathogenesis of esophageal squamous cell carcinoma (ESCC). Previous studies regarding the association of folate intake and Methylenetetrahydrofolate reductase C677T polymorphism with ESCC was conflicting. We conducted a meta-analysis to investigate the association of MTHFR C677T and folate intake with esophageal cancer risk.Methodology: MEDLINE, EMBASE and the Chinese Biomedical Database were searched in our study. The quality of studies were evaluated by predefined scale, and The association of polymorphisms of MTHFR C677T and folate intake and ESCC risk was estimated by Odds ratio (ORs) with 95% confidence intervals (CIs).Results: Nineteen studies (4239 cases and 5575 controls) were included for meta-analysis. A significant association was seen between individuals with MTHFR 677 CT [OR(95%)=1.47(1.32-1.63)] and TT [OR(95%)=1.69(1.49-1.91)] genotypes and ESCC risk (p<0.05). Low intake of folate had significantly higher risk of esophageal cancer among individuals with CT/TT genotype [OR(95%)=1.65(1.1-2.49)], while high intake of folate did not find significant high risk of esophageal cancer among individuals with CT/TT genotype [OR(95%)=1.64 (0.82-3.26)].Conclusions: Our meta-analysis indicated the folate intake and MTHFR 677CT/TT are associated with the risk of ESCC, and folate showed a significant interaction with polymorphism of MTHFR C677T. Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancer in China, and it is estimated 250,000 cases are diagnosed annually. Possible risk factors for ESCC include cigarette smoking, alcohol drinking, hot-temperature food, low intake of vegetable, salted food, pickled vegetables, chronic mucosal irritation and a family history of cancer.1-6 Deficiency of nutrients, such as vitamins and microelements, was suggested to be associated with an increased risk for ESCC.6Esophageal squamous cell and adenocarcinoma are common malignancies worldwide7 Deficiency of folate could induce defective DNA repair and chromosomal fragile site expression, leading to chromosomal breaks and micronucleus formation.8 Methylenetetrahydrofolate reductase (MTHFR) C677T in the gene encoding the MTHFR enzyme, which converts dietary folate to its active cofactor in Hcy catabolism, has been studies as candidate genetic risk factor for esophageal cancer.9 As T allele dose increases, this functional polymorphism causes a graded elevation in individuals with low dietary folate consumption.10Folate is a water-soluble vitamin and naturally found in green leafy vegetables, cereals, legumes and fruits.9,11,12 The variation of these results might be induced by difference in ethnicities, sample size, study design and background of patients as well as random error. Therefore, we conducted a systematic review to investigate the association of MTHFR C677T and folate intake with esophageal cancer risk by reducing random error and obtaining precise estimates for some potential genetic associations.13Therefore, several previous studies have investigated the association of MTHFR C677T and folate intake with esophageal cancer risk, but the results are conflicting.MTHFR C677T polymorphisms and ESCC; (2) original study and an available genotype or allele frequency of MTHFR C677T genotypes for estimating an odds ratio (OR) with a 95% confidence interval (CI). If the results of a study reported two or more times on the same patient populations, only the most recent and complete study was included in our study.We searched MEDLINE (from Jan. 1966 to Jan. 2011), EMBASE (from January 1988 to Jan. 2011), and the Chinese Biomedical Database  by using the following search strategy for published papers: ‘esophageal squamous cell carcinoma’, ‘esophagus’, ‘oesophagus’, ‘carcinoma or cancer or neoplasm or tumour or tumor’, ‘Methylenetetrahydrofolate reductase’, or ‘MTHFR’. There was no restriction on the language of published paper. All references cited in studies and previously published review articles were retrieved for additional eligible studies. The eligible criteria for including studies were (1) a case-control study reporting an association between Data extraction: Two reviewers independently evaluated the retrieved articles, and the disagreements were resolved by discussion. Data retrieved from selected articles was included. In case the data were insufficient or missing, we attempted to contact the authors of the articles in order to request the relevant data. From those studies which werefinally selected, we extracted the following data: first author’s name, year of publication, country of origin, numbers of cases and controls, genotype frequencies of MTHFR C677T.Quality score assessment: The quality of studies was evaluated by predefined scale in previous studies14 . The distributions of genotypes in controls were tested by Hardy-Weinberg equilibrium (HWE) using the Chi-square test. The association of polymorphisms of MTHFR C677T and folate intake and ESCC risk was estimated by Odds ratio (ORs) with 95% confidence intervals (CIs). The heterogeneity was tested by the Q-statistics with p-values < 0.1, and its possible sources of heterogeneity were assessed by subgroup analysis. If there was heterogeneity, the random effect model was used. Otherwise, a fixed-effect model was applied to obtain the summary OR and their 95% CI. One-way sensitivity analysis was performed to explore robustness of the results. All P values were two-sided and a P value of less than 0.05 was deemed statistically significant.Characteristics of studies: Forty seven studies were initially identified after search, and 28 studies were excluded due to overlapping data and being without meeting the criteria. Finally, 19 studies (4239 cases and 5575 controls) were included for meta-analysis. The detailed characteristics of these studies are summarized in MTHFR 677 CT [OR(95%)=1.47(1.32-1.63)] and TT [OR(95%)=1.69(1.49-1.91)] genotypes and ESCC risk (p<0.05). There was significant heterogeneity between studies regarding MTHFR 677 CT and TT (P<0.05).A significant association was seen between individuals with Subgroup analysis was taken according to folate intake, which indicated low intake of folate had significantly higher risk of esophageal cancer among individuals with CT/TT genotype [OR(95%)=1.65(1.1-2.49)] . HoweverMTHFR 677 CT, but a significant publication bias was found in studies regarding MTHFR 677TT genotype(P<0.05). The shape A of funnel plots was asymmetrical . Funnel plot an Egger’s test were used to assess the publication bias, and it provided evidence that there was no publication bias among studies regarding metrical  and 2.MTHFR C677T for EC risk provided inconsistent results. Most of those studies involved few cases, and these few sample size limited the genetic effect reliabilty. Our meta-analysis recognized as an important tool to more precisely define the effect of selected genetic polymorphisms on risk of disease and to identify the potentially important sources of between-study heterogeneity. A previous meta-analysis in Asian population included 13 case-control studies which indicated MTHFR 677 CT and TT genotypes were significantly association with increased risk of esophageal cancer, especially in drinkers and smokers.30 However, this study did not explore the interaction between folate intake and MTHFR genotype. Therefore, we conducted an updated meta-analysis by critically reviewing 19 individual case-control studies on MTHFR C677T and folate intake with esophageal cancer risk. Compared with the last meta-analysis conducted in China by Fang et al, this updated meta-analysis included another 6 new case-control studies, and we explored the interaction between folate intake and MTHFR C677T. Our study showed that high intake of folate had a protective factor for esophageal cancer, and folate showed a significant interaction with polymorphism of MTHFR C677T.Many epidemiologic studies which investigated the role of folate intake and 31 In our study, we found there was significant heterogeneity between studies by using Q-statistics. However, after stratifying by the quantity of folate intake suggested folate was an important source of heterogeneity.Heterogeneity is a potential problems in the meta-analysis, and eliminating heterogeneity is an important factor during meta-analysis.32 These functions may play a critical role in carcinogenesis. Previous epidemiological studies have indicated an abundant intake of food stuffs full of folate could protect the development of various cancers.33 Ours study indicated that the folate intake was associated with a decreased risk of esophageal cancer, which proved previous hypothesis. Moreover, the activity of folate metabolic enzyme, such as MTHFR, are involved in the folate metabolic and DNA methylation process. As a key enzyme in folate metabolism, the product of MTHFR serves as the carbon donor for the methylation of homocysteine tomethionine, which is catalyzed by the enzyme MTR.34 The MTHFR gene is high polymorphic in the general population, the mutation of most common functional variant of 677C to T. This polymorphism results in an alanine to valine substitution, leading to a reduction in enzyme activity.35 The role of MTHFR in the folate metabolism decides the interaction between folate and polymorphisms of MTHFR, which was proved by our meta-analysis. Our study showed the MTHFR had strong risk of esophageal cancer in individuals with low intake of folate intake.Previous studies have indicated folate mediates the transfer of one-carbon moieties both in the synthesis of nucleotides necessary for DNA synthesis, replication, repair and in DNA methylation reactions.Possible limitations of this meta-analysis have to be considered in explaining our results. Firstly, most of the studies are conducted in China, and this could limit the power to find the difference in genotypes by different ethnicities. Secondly, publication bias may have occurred due to only published papers which were included in the meta-analysis. Thirdly, there might be misclassification during our study. Some controls in our study were selected from non-cancer inpatients, and some were selected from residents. Finally, there might be gene-environment interaction for esophageal cancer. However, we did not perform subgroup analysis due to lack of data on environmental factors. Further studies are warranted to interpreted this interaction.MTHFR 677CT/TT are associated with the risk of ESCC, and folate showed a significant interaction with polymorphism of MTHFR C677T. In conclusion, our meta-analysis has indicated the folate intake and


ADRB2) gene has been widely researched as a candidate gene for essential hypertension (EH), but no consensus has been reached in different ethnicities. The aim of the present study was to evaluate the possible association between the ADRB2 gene polymorphisms and the EH risk in the Northern Han Chinese population.The β2-adrenergic receptor  than that in controls. Significant association could also be found in dominant genetic model , in homozygote comparison , and in additive genetic model . Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Stratification analyses by obesity showed that A46G polymorphism was related to the prevalence of hypertension in the obese population . Significant interaction was found between A46G genotypes and body mass index on EH risk. No significant association could be found between C-47T or C79G polymorphism and EH risk. Linkage disequilibrium was detected between the C-47T, A46G and C79G polymorphisms. Haplotype analyses observed that the T-47-A46-C79 haplotype was a protective haplotype for EH, while the T-47-G46-C79 haplotype increased the risk.This study included 747 hypertensive subjects and 390 healthy volunteers as control subjects in the Northern Han Chinese. Genotyping was performed to identify the C-47T, A46G and C79G polymorphisms of the ADRB2 A46G polymorphism might increase the risk for EH in the Northern Han Chinese population.We revealed that the  ADRB2) has been investigated worldwide, since in hypertension vascular responses to ADRB2 stimulation are impaired ADRB2 gene polymorphisms appear to affect vasodilation Essential hypertension (EH) is a worldwide escalating problem. In China, it was reported that 27.2% of the adult population age 35 to 74 years suffered from it ADRB2 gene in hypertension has been extensively evaluated. In vitro, the research ADRB2, displayed normal agonist binding and functional coupling to the stimulatory form of G protein (Gs), resulting in the stimulation of adenylyl cyclase activity. In vivo, it was reported that both polymorphisms might contribute to enhanced vascular reactivity to isoproterenol in capacitance vessel, which played a part in the regulation of blood pressure ADRB2 expression at a translational level At the molecular level, the role of the A substantial number of studies have previously investigated the association between the A46G, C79G and C−47T polymorphisms and EH risk. Several of these failed to identify any association A total of 1,137 unrelated participated subjects comprising 747 hypertensive patients  and 390 normotensive control subjects  were recruited for the present study. The clinical and laboratory parameters of cases and controls were summarized in ADRB2 were shown in Among all the participants, 99.3% samples of C-47T polymorphism, 98.3% samples of A46G polymorphism and 97.7% samples of C79G polymorphism were successfully tested in the laboratory. No deviation from Hardy-Weinberg expectation was observed for C-47T, A46G or C79G polymorphism in either hypertensives or normotensives. The genotype frequencies for the 3 polymorphisms in Logistic regression analysis was performed after adjusting for confounding risk variables, that is, gender, age, BMI, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum triglyceride levels, plasma glucose level, smoking habits and drinking habits. For A46G polymorphism, we observed a significantly higher prevalence of G allelic frequencies  in the hypertensives than the normotensives, which suggests that G allele might be a risk factor for hypertension in the Northern Han Chinese. Significant association could also be found in dominant genetic model , in homozygote comparison , and in additive genetic model . No significant association could be found between C-47T or C79G polymorphism and EH risk.  SubgroupADRB2 gene polymorphisms on hypertension, we analyzed the relation between C-47T, A46G and C79G polymorphisms and hypertension by stratification analyses. All the participants were divided into the obese subgroup and the non-obese subgroup according to BMI. The case-control study was further performed in both subgroups. To explore the interactive effect of obesity and the 2 = 0.98). LD could also be found in C-47T and A46G , as well as in A46G and C79G . The Haploview program revealed C-47T, A46G and C79G polymorphisms in the same LD block. The haplotype analyses of the 3 polymorphisms of ADRB2 in hypertension and control subjects were shown in ADRB2 gene between cases and controls . Haplotype specific (HS) testing showed that the T-A-C haplotype was a protective haplotype  while the T-G-C haplotype was observed to be a risk . The C-G-G haplotype was not associated with EH in the Northern Han Chinese (P = 0.292).As shown in The relative effects of the haplotypes were evaluated by the logistic regression. As the most highly prevalent haplotype, the T-A-C haplotype was defined as the base-line haplotype. Comparing with the base-line haplotype, the T-G-C haplotype was associated with a risk to EH . No association could be found between the C-G-G haplotype and EH (P = 0.089).ADRB2 gene was associated with EH in the Northern Han Chinese. G46 allele had a significantly higher representation in the cases than in the controls. These findings were consistent with another study among the Northern Han Chinese on stage 2 hypertension diagnosed on systolic blood pressure (SBP)≥160 mmHg and/or diastolic blood pressure (DBP)≥100 mmHg reported by Gu et al. and Ge et al. et al. and Ge et al.'s study et al. and Ge et al.'s study et al. and Ge et al.'s. For the low frequency of the uncommon allele of C79G, extremely large trial size was required for enough statistical power to detect real differences between groupset al. and Ge et al.'s study. As for the C-47T polymorphism, both studies got negative results. Negative results were also found on C79G polymorphism in our case-control study since it was almost in complete LD with C-47T, which was different from Gu et al. and Ge et al.'s. Previous research also reported different degree of LD between C79G and C-47T in different ethnic background subjectset al. and Ge et al.'s were not entirely enrolled from the same area, the participants were not in a single homogenous populationThe present study found that the A46G polymorphism of the et al. et al.'s comparison on the control subjects. When both research studied on the same kind of participants, the non-obese population, and compared between hypertension and normotension, our findings were consistent with Mo et al.'s result. Furthermore, with the genetic background difference Stratification analyses showed that A46G polymorphism was association with EH risk in male, but not in the female population. No significant interaction existed between A46G genotype and gender. Yet we suggested that the different results between men and women and the P-value for genotype-gender interaction should be treated cautiously, as the women participants in this study were considerably smaller than men, which might limit the power to detect differences in OR estimates between the subgroups. Stratification analyses on obesity found the association between A46G polymorphism and EH risk in the obese subgroup, both in obese men and in obese women, whereas in the non-obese population, no association could be found. Significant interaction could also be found between A46G genotypes and BMI on EH risk. These findings suggested that obesity might have an effect on the association between genetic factors and EH risk. Mo Compared with the studies on Caucasians et al.Haplotype analyses suggested that only 3 haplotypes with frequency greater than 1% were found in the study as previously described et al. reported et al.As Green ADRB2 gene controlled the ADRB2 expression. The T-47 allele resulted in increased expression of the ADRB2 as compared with the C-47 allele. As the LD between the C-47T polymorphism and the ADRB2 gene coding block polymorphisms A46G and C79G, it suggested that the allele frequency of the C-47T polymorphism associated with that of the A46G and C79G polymorphisms. In other words, the A46G and the C79G variants within the coding region were thought to affect the ADRB2 gene expression. The current study found that the A46G polymorphism, but not the C79G or C-47T polymorphism, associated with the risk of EH in the Northern Han Chinese population. However, for the tight LD between multiple polymorphisms on the ADRB2 gene, we believe that the A46G polymorphism should not be independently considered as the impact factor of the ADRB2 gene on the pathogenesis of EH. Further research on the role of the multiple polymorphisms of different regions within the ADRB2 gene in the pathophysiologic of EH are important to clarify the genetic mechanism of EH.It was reported ADRB2 gene polymorphisms in different ethnicities and the low minor allele frequencies of C-47T and C79G polymorphisms, larger case-control studies stratified for different ethnicities should be performed to clarify the association between the ADRB2 gene polymorphisms and EH risk in the future.Compared with early studies, the sample size of the present study was moderate. However, for the minor allele frequencies of C-47T, A46G and C79G of the Asians were significantly lower than that of the Caucasians and the Blacks as previously reported ADRB2 gene significantly associated with EH risk among the Northern Han Chinese population. The G46 allele was a risk factor for EH. Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Stratification analyses by obesity showed that G46 allele was related to the prevalence of hypertension in the obese population. Significant interaction existed between A46G genotypes and BMI on EH. Haplotype analyses suggested that the T-47-A46-C79 haplotype was a protective haplotype for EH, while the T-47-G46-C79 haplotype increased the risk of EH. Furthermore, for the tight LD between the polymorphisms in the ADRB2 gene, further research is warranted to elucidate the role of the multiple polymorphisms within the ADRB2 gene in the mechanism of EH.In conclusion, we found that the A46G polymorphism in the The study complies with the Declaration of Helsinki, the local ethics committee of Beijing Anzhen Hospital of the Capital University of Medical Sciences has approved the research protocol. Written informed consent was obtained from each participant.All individuals were of Northern Han Chinese origin and from the Beijing area recruited range from June 2008 to June 2009 in this study. All the participants were ascertained and identified via Anzhen Hospital of the Capital University of Medical Sciences, Beijing, China (n = 859), and two examination centers at local health stations, Liuliqiao (n = 71) and Guozhuang (n = 207), in Beijing suburbs.2 according to the World Health Organization obesity guidelines on Asians Blood pressure was measured by trained and certified observers according to a common protocol adapted from procedures recommended by European Society of Hypertension ADRB2 SNP Taqman probes and primers were obtained from Applied Biosystems Assay-by-Design Service for SNP genotyping. The sample DNA was amplified by PCR following the recommendations of the manufacturer. Thermal cycling was done on a GeneAmp PCR System 9700 thermal cycler . Genotypes were differentiated by analyzing the fluorescence levels of PCR products using an ABI PRISM 7900HT Sequence Detector (Applied Biosystems). Genotyping was performed blindly to all other data.Blood was taken into EDTA-containing receptacles. Genomic DNA was extracted from peripheral blood according to standard phenol-chloroform methods. We genotyped SNPs using the TaqMan assay. The We used SPSS  for database management and statistical analyses. All comparisons between specific groups for continuous variables were made using a two-sample t-test. Allelic and genotypic frequencies were compared between the hypertensive cases and the normotensive controls by using the chi-square test. Genotype frequency of the subjects specified by different genetic models  was analyzed by multivariate logistic regression adjusted for covariates. Analyses used two-tailed estimation of significance. The statistical significance was defined P<0.05.http://ihg.gsf.de/cgi-bin/hw/hwa1.pl).The presence of Hardy–Weinberg equilibrium was tested by the chi-square test for goodness of fit based on a web program (ADRB2 gene was based on genotypes and utilized Haploview software (version 4.1) (http://www.broad.mit.edu/mpg/haploview/) http://analysis.bio-x.cn/myAnalysis.php) Construction of the LDmap and haplotype blocks within C-47T, A46G and C79G polymorphisms of the