Chronic hepatitis B (CHB) infection during pregnancy is associated with insulin resistance. A meta-analytic technique was used to quantify the evidence of an association between CHB infection and the risk of gestational diabetes (GDM) among pregnant women.We searched PubMed for studies up to September 5th 2013. Additional studies were obtained from other sources. We selected studies using a cohort-study design and reported a quantitative association between CHB infection during pregnancy and risk of GDM. A total of 280 articles were identified, of which fourteen publications involving 439,514 subjects met the inclusion criteria. A sequential algorithm was used to reduce between-study heterogeneity, and further meta-analysis was conducted using a random-effects model.Ten out of the fourteen studies were highly homogeneous, indicating an association of 1.11  between CHB infection during pregnancy and the risk of developing GDM. The heterogeneity of the additional four studies may be due to selection bias or possible aetiological differences for special subsets of pregnant women.These results indicate that CHB infection during pregnancy is not associated with an increased risk of developing GDM among pregnant women except those from Iran. The hepatitis B virus (HBV) accounts for significant morbidity and mortality worldwide . An estiGDM is defined as glucose intolerance with an onset or first recognition during pregnancy. Asian women, including Chinese women, have been found to have the highest incidence of GDM . Women wSimilarly to CHC infection, CHB infection is considered to be associated with insulin resistance (IR) , which iTo address these issues, we performed a meta-analysis of cohort studies to investigate whether CHB infection during pregnancy is associated with an increased risk of GDM.http://edmgr.ovid.com/ong/accounts/moose.pdf). Two independent investigators (Kong and Liu) searched PubMed from 1966 to September 5th, 2013 using the combinations of terms “hepatitis B” or “hepatitis B surface antigen (HBsAg)” and “pregnancy outcome” or “prenatal outcome” or “perinatal outcome” or “gestational diabetes”. We sifted through potentially relevant articles, firstly by titles and abstracts, and then we retrieved the full texts of articles for detailed review. Further, we scanned the reference lists of the articles that met the inclusion criteria in our analysis, and searched for those articles or citations in the Web of Knowledge, Google Scholar and Google to obtain additional studies.This meta-analysis was conducted in compliance with the Meta-Analysis of Observational Studies in Epidemiology guidelines  in blood during the first prenatal care visit, on admission to the labour ward, or before delivery. GDM diagnosis was performed according to the recommended clinical practice.A form designed a priori was used to extract the information from the included studies. Two independent investigators (Han and Wei) performed the data extraction. A third investigator (Wang) examined the results, and a consensus was considered as agreement between at least two out of the three investigators. GDM was the primary outcome measure. We extracted the following data Table : authorsTwo independent investigators (Kong and Hu) evaluated the quality of each study using the Newcastle-Ottawa Quality Assessment Scale (NOS) . The thiThe cross-study effect of CHB infection vs. non-CHB control on the risk of GDM was measured using the odds ratios (OR) with 95% confidence intervals (CIs), which were reported as the effect measurements in all of the included studies except for one , which ra) was automatically included in our analysis; the unadjusted or crude OR (ORc) was corrected using external estimates of confounding by the method of coefficient adjustment introduced by Greenland   of the subjects among the fourteen studies, and together reported a GDM prevalence of 6.30% 884/14,028) among pregnant women with CHB infections and 3.63%  among uninfected pregnant women. The association between CHB infection during pregnancy and the risk of developing GDM was 1.11 [the adjusted odds ratio , designs , epidemic levels , and GDM diagnostic criteria.Subgroup and meta-regression analysis showed that the pooled ORa from the ten studies demonstrated a possible publication bias. After trim and fill methods were performed, the pooled ORa was 1.10  . These findings suggest that CHB infection during pregnancy is not associated with an additional risk of GDM.Those ten homogeneous studies reported GDM prevalences of 6.30% and 3.63% among pregnant women with and without CHB infection, respectively. The risk of GDM for CHB-infected pregnant women was comparable to the risk for uninfected women . IR has been shown to be associated with both CHC and CHB infection , but CHCRoutine screening for GDM is recommended near the beginning of the third trimester, and the identification of GDM will depend on the diagnostic criteria and guidelines. For economic, psychological and other reasons, GDM screening is conducted using a risk factor-based selective screening approach in most countries rather than universal screening. These differences in strategies did not seem to affect the non-significant association between CHB infection and the risk of GDM -14,16,17Our findings imply that GDM is not attributable to CHB infection during pregnancy. Thus, any extra GDM screening for this population is not necessary, which is a commonly accepted practice throughout the world except in Hong Kong, China. This extra screening will likely result in a greater economic burden and additional psychological concerns such as fear or guilt, especially in epidemic areas, like China. Probably, advanced clinical stages of liver diseases of varied aetiologies may be more important in the development of GDM, and the significantly high association between CHB infection and GDM in Iranian pregnant women is worth further study.The authors declare that they have no competing interests.YZ and YL conceived and coordinated the study and drafted the manuscript. DK and HL participated in the study design, reference search and data analysis. WH and SW participated in the study design and data extraction. DK and AH participated in the quality rating and data analysis. YW and YL participated in the quality rating and the data extraction and analysis. NZ supervised the statistical analysis. All authors read and approved the final manuscript.Flow chart describing the paper retrieval and analysis strategies for this meta-analysis. GDM: gestational diabetes mellitus; CHB: chronic hepatitis B infection.Click here for file


LRP5) was identified to be linked to the variation in bone mineral density and types of bone diseases. The present study was aimed at examining the association of LRP5 rs3736228 C>T gene with bone fracture and osteoporosis by meta-analysis. A systematic electronic search of literature was conducted to identify all published studies in English or Chinese on the association of the LRP5 gene with bone fracture and osteoporosis risks. All analyses were calculated using the Version 12.0 STATA software. Odds ratios (ORs) and their corresponding 95% confidence interval (95% CI) were calculated. An updated meta-analysis was currently performed, including seven independent case-control studies. Results identified that carriers of rs3736228 C>T variant in the LRP5 gene were associated with an increased risk of developing osteoporosis and fractures under 4 genetic models but not under the dominant model . Ethnicity-subgroup analysis implied that LRP5 rs3736228 C>T mutation was more likely to develop osteoporosis and fractures among Asians and Caucasians in majority of subgroups. These results suggest that there is a modest effect of the LRP5 rs3736228 C>T on the increased susceptibility of bone fracture and osteoporosis.The low-density lipoprotein receptor-related protein 5 gene ( Bone fracture, mainly caused by decrease in bone strength associated with bone loss, has contributed to an increase in disability, morbidity, death, and health expenses , 2. Acco LRP5 gene is located on chromosome 11q13.4 and consists of 22 introns and 23 exons, spanning approximately 160 kb [ LRP5 gene contribute to subsequent reduction of bone mineral density (BMD), indicating a dominant negative effect on bone mass, which would lead to various bone diseases [ LRP5 gene have been detected in correlation with bone phenotypes, including fracture risk and BMD, among which a coding single nucleotide polymorphism (SNP) of the LRP5 gene, rs3736228 (A1330V), is thought to have a particular susceptibility to osteoporosis [ LRP5 gene could be regarded as a useful genetic biomarker for the prediction of osteoporosis and bone fracture [ LRP5 gene and the risk of bone fracture, as well as osteoporosis. This study aimed to give an overall view of this subject and further evaluate its role as a biomarker in predicting the pathogenesis of osteoporosis.Lipoprotein receptor-related protein 5 (LRP5), as a member of the low-density lipoprotein receptor family, is a single-pass plasma membrane protein secreted in many tissues and cells, such as breast tissues, bone tissues, endothelial cells, and stem cells , 14. Humy 160 kb . It has y 160 kb , 18. Howdiseases , 19. A foporosis , 21. ThePotential relevant studies were identified by a comprehensive literature search in April 30, 2014, which included the following computerized bibliographic databases: MEDLINE (1966~2014), Science Citation Index (1945~2014), Cochrane Library , PubMed (1966~2014), Embase (1974~2014), CINAHL (1982~2014), and Current Contents Index (1995~2014). In addition, Chinese Biomedical (1978~2014), Chinese Journal Full-Text (1980~2014), and Weipu Journal (1989~2014) were also used to identify Chinese articles. We used medical subject headings and free language terms with a highly sensitive search strategy, the search terms were as follows: “Fractures, Bone” or “Broken Bones” or “Fractures” or “Fracture” or “Broken Bone” or “Bone Fractures” or “Bone Fracture” and “OP, Postmenopausal” or “OP” or “Juvenile OP” or “OP” or “Osteoporoses” or “Age-Related Bone Loss” or “Age-Related OP” or “Age-Related OP” and “LRP5 protein, human” or “LRP5” or “low density lipoprotein receptor-related protein 5” or “LDL receptor-related protein 5.” No restrictions were made with respect to language, country, or data collection. Manual searches were also used to identify other potential articles. Further trials were sought from reference lists in the relevant papers to find additional works which failed to be captured by electronic or manual searches. LRP5 (rs3736228) polymorphism and susceptibility to osteoporosis and fracture were incorporated into the meta-analysis; (3) all subjects underwent diagnostic evaluations and satisfied the clinical diagnosis of osteoporosis or fracture confirmed by the report of the World Health Organization Task-Force for Osteoporosis [ LRP5 gene; (5) distributions of genotype frequencies in LRP5 (rs3736228 C>T) were within the range of Hardy-Weinberg equilibrium (HWE) in the controls; (6) once studies provided overlapping data, we would choose the study that had the largest sample size. The major exclusion criteria in this meta-analysis were as follows: (1) some publication types presenting nonoriginal data, such as letters, editorials, abstracts, reviews, meta-analysis opinion papers or proceedings; (2) unpublished sources of data; (3) duplicated publications or studies without extractable, numerical data; (4) subgroup analysis of the included trials. Based on these inclusion/exclusion criteria, the title and abstract of all the retrieved articles were evaluated for relevance, and then the full texts of the selected articles were reviewed, followed by a decision on their eligibility for inclusion in this systematic review.To be included in the systematic review, retrieved studies had to be assessed with two observers (Jia-Li Liu and Yong-Bing Xiang) for their suitability for meeting the following criteria: (1) case-control studies published on peer-reviewed journals; (2) only those studies examining the associations between SNPs inoporosis , 24; (4)In order to ensure consistency in reviewing and reporting results, two reviewers independently assessed the methodological quality of the included trials using the Newcastle-Ottawa Scale (NOS) criteria with study design, content, and ease-of-use in the explanation of results or the meta-analysis for assessing the quality . The thrEach of the two reviewers assessed the studies independently based on the inclusion/exclusion criteria mentioned before to the methods section. We used a standardized data form in duplicate to collect the following descriptive information: surname and initials of the first author, the year of publication or submission, journal, source country, racial descent of study population, language of publication, study design, number of cases and controls, source of controls, demographic variables of the subjects, SNP information, detection method of genotypes, genotype frequencies, allele frequencies, HWE test and confirmation of diagnosis, and so forth. Disagreement on the inclusion of a single study was settled by discussion, or a third investigator was consulted. LRP5 (rs3736228 C>T) with bone fracture and osteoporosis. A 95% confidence interval (95% CI) was calculated for the summary OR by the use of Z  test. The pooled ORs were carried out for the comparison in allele model , dominant model (WW + WM versus MM), recessive model (WW versus WM + MM), homozygous model (WW versus MM), and heterozygous model (WW versus WM), respectively. Also, in order to explore for heterogeneity other than threshold effect, a test for heterogeneity between trials included for each comparison was performed by the use of the Cochran's Q-statistic and I2 tests [Q-test showed evidence of a P < 0.05 or I2 test exhibited > 50%, indicating maximal heterogeneity among the included studies, we did metaregression analysis to explore sources of heterogeneity with a random-effects model by relating study level covariates to diagnostic OR, and otherwise ORs were pooled according to the fixed-effects model [ LRP5 (rs3736228 C>T) (and 95% CI) were evaluated for subgroups of different explanatory variables. Additionally, in order to evaluate the impact of single studies on the overall estimate, a one-way sensitivity analysis was employed to ensure that no single study was completely responsible for the overall results. Further, Egger's linear regression test with visual inspection of the funnel plot was applied to detect the potential publication bias [We calculated the odds ratios (ORs) and their corresponding 95% confidence interval (CI), for the purpose of evaluating the relationship of the SNP in2 tests . If the ts model , 28. Wheion bias , 30. StaThe combined electronic and manual search initially resulted in 278 potentially eligible articles. After the exception of 2 duplicated studies, 276 retrieved studies were screened by title and abstract for relevance; subsequently, 161 irrelevant articles were excluded. Then, we systematically reviewed the remaining 115 articles qualified for full-text reading, and 106 articles were deemed unsuitable and were therefore excluded. Thus, 9 articles were identified to be included in quantitative analysis. In addition, another 2 studies were excluded due to lack of data integrity after a more careful assessment of the remaining articles. Finally, 7 studies composed of 2,772 subjects including 907 patients and 1,865 control subjects were incorporated into this meta-analysis , 31–35.  LRP5 (rs3736228 C>T) in fracture patients and the controls; the other 5 studies were concerned about the genotype/allele frequencies of LRP5 (rs3736228 C>T) in osteoporosis patients and the controls. Additionally, of the 7 studies included in the analysis, 3 were performed in Caucasians and the other 4 were in Asians. The controls were drawn from population-based sources and hospital-based sources. With respect to the genotyping methods, two studies were performed with non-TaqMan assay (direct sequencing and pyrosequencing), and the other five studies were conducted with TaqMan assay. The information of the SNPs (rs3736228 C>T) in the LRP5 gene was included to evaluate the association between polymorphic variants of the LRP5 gene and the risk of osteoporosis and fractures. From the 7 included studies, 2 studies focused on the genotype/allele frequencies of LRP5 gene was identified, and the association between the allelic and genotypic frequencies of LRP5 rs3736228 C>T and the risk of osteoporosis and fractures were investigated. Results in this meta-analysis demonstrated that the carriers of the rs3736228 C>T polymorphism in the LRP5 gene were associated with an increased risk of developing osteoporosis and fractures in the allele model, whereas the dominant model of LRP5 rs3736228 C>T showed no statistically significant differences between the cases and controls derived from the 7 included studies   . LRP5 rs3736228 C>T polymorphism-containing populations were more likely to develop osteoporosis and fractures in the Caucasians under both the allele and dominant models , yet similar results were not observed among Asians (P > 0.05)  and in recessive model, homozygous model, and heterozygous model in the hospital-based subgroups  (P = 0.037) and fractures in the in recessive, homozygous, and heterozygous models . When concerned about the genotype method-stratified subgroups, it has been revealed that the rs3736228 C>T polymorphism carriers in the allele, recessive, homozygous, and heterozygous models were related to significantly higher osteoporosis and fractures susceptibility in the TaqMan assay subgroup , yet it showed none significant association regarding the rs3736228 C>T polymorphism and higher risks of osteoporosis and fractures in the non-TaqMan assay subgroup under 5 genetic models  (P > 0.05)  . For the > 0.05) . However > 0.05) .t = −0.12, P = 0.908) and rs3736228 C>T dominant model  in systematic reviews  receptor family, LRP5 may bind and internalize ligands in the process of receptor-mediated endocytosis and also play a crucial role in skeletal homeostasis [β-catenin canonical pathway [ LRP5 gene have been reported to be associated with the risk of bone fracture and osteoporosis [ LRP5 genetic polymorphisms might cause loss of function of LRP5, decrease the signaling activity of the canonical Wnt signaling pathway, and lead to reduced bone formation, thereby conducing to the development of bone fracture and osteoporosis [ LRP5 gene might be consistently linked to bone mineral density and the risk of bone fracture across different white populations [ LRP5 genetic polymorphisms seem to be possible genetic determinants for susceptibility to idiopathic osteoporosis in males [The present meta-analysis aggregated large-scale evidence from relevant studies in an attempt to determine whether rs3736228 C>T polymorphism in theeostasis , 36. In  pathway . It has  pathway . Recentloporosis , 39. Actoporosis . Consistulations . Ferrariin males . LRP5 rs3736228 C>T polymorphism might be closely implicated in the pathogenesis of bone fracture and osteoporosis, implying that this polymorphism may be a helpful biomarker in predicting the occurrence of bone fracture and osteoporosis.Results of ethnicity-stratified analysis revealed that rs3736228 C>T variant might be connected with bone fracture and osteoporosis risks among Caucasians but not among Asians. Type of disease-stratified analysis indicated that rs3736228 C>T mutation might be related to the development of osteoporosis, but this polymorphism may not be a predictive factor for the etiology of bone fracture. In summary, the discovery of the represented meta-analysis was in conformity with previous studies that LRP5, especially the rs3736228 C>T variant, and the increased susceptibility to bone fracture and osteoporosis, comprehensively and systematically. Additionally, all included literatures had acceptable quality scores . However, some limitations of this meta-analysis should also be acknowledged when interpreting the results. Firstly, the current analysis was only limited to one single SNP (rs3736228 C>T) that is being widely discussed in various researches, while other SNPs have also been researched to be related to bone fracture and osteoporosis risk. One of the major concerns may be the bias due to selective publication and language bias derived from the fact that the screened references of papers published in languages other than English and Chinese were not included. Secondly, the crude division criteria of ethnic groups into “Caucasians,” and “Asians” promoting the study are prone to bias. All studies were performed in Asians and Caucasians; to capture the full range of possible ethnic differences in LRP5 rs3736228 C>T polymorphisms, further studies are needed in other ethnic groups, such as among Africans. Thus, deeper investigation from different populations is warranted to clarify the present results. Another important concern should take into consideration that different diseases have different risk factors and diverse sensitivities to them. In particular, we did not evaluate family history and clinical implication of bone fracture or osteoporosis in our study since we did not collected those information at baseline. Finally, the present sample size did limit the power to identify LRP5 rs3736228 polymorphism with a small influence on bone fracture and osteoporosis.Indeed, some advantages could be highlighted in this meta-analysis. One of the major superiorities may be that the present research shed lights on the relation of genetic polymorphisms in LRP5 gene may increase the risk of bone fracture and osteoporosis. SNP in the LRP5 gene may considerably act as a potential candidate of biomarker for bone fracture and osteoporosis screening, diagnosis, and future treatment. To certain the current results, updated well-designed researches with larger sample size, in diverse ethnic populations particularly, are required in the future.In summary, this meta-analysis suggests that rs3736228 C>T variant in the


CETP)-TaqIB polymorphism as an instrument based on Mendelian randomization.Recent randomized controlled trials have challenged the concept that increased high density lipoprotein cholesterol (HDL-C) levels are associated with coronary artery disease (CAD) risk reduction. The causal role of HDL-C in the development of atherosclerosis remains unclear. To increase precision and to minimize residual confounding, we exploited the cholesteryl ester transfer protein . The result was not materially changed after excluding the Hardy-Weinberg Equilibrium (HWE)-violation studies. Compared with B1B1 homozygotes, Caucasian carriers of the B2 allele had a 0.25 mmol/L increase in HDL-C level . However, a 1 standard deviation (SD) elevation in HDL-C levels due to the TaqIB polymorphism, was marginal associated with CAD risk .The overall comparison of the B2 allele with the B1 allele yielded a significant risk reduction of CAD  with substantial between-study heterogeneity  contains supplementary material, which is available to authorized users. Several clinical parameters are associated with common diseases and are helpful for predicting and preventing these common diseases. For instance, lipid profiles are well acknowledged to be associated with the risk of coronary artery disease (CAD) and myocardial infarction (MI) . ObservaCETP locus with HDL-C concentrations is more significant than that of any other locus found across the genome [CETP gene to CAD, it would be sensible to conduct a meta-analysis that in some way integrates the triangle relationship: the TaqIB polymorphism-HDL-C (genotype-phenotype), the TaqIB polymorphism-CAD (genotype-disease), and HDL-C-CAD (phenotype-disease). The logic of this approach is greatly strengthened by the appeal to Mendelian randomization [CETP plays a key role in determining the circulating HDL levels and transfers cholesteryl esters from HDL-C to LDL-C, as well as very low density lipoprotein cholesterol (VLDL-C), in exchange for triglyceride rich lipoproteins . An invee genome ,13. Amone genome  has beene genome . Signifie genome  and circe genome  were obse genome ,17-19. He genome ,19-23, mmization , which imization . Mendelimization .Two authors (Wu and Lou) independently performed the search. The process was supervised by the third author (Qiu). Any disagreement was resolved by a consensus. The advanced search builder was used to refine the search. The Boolean operators “AND” and “OR” were used to combine the search themes. A stepwise search was conducted as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). A formal computerized literature search of electronic databases, PubMed/MEDLINE, Embase, CNKI (China Nation Knowledge Infrastructure Platform), Wanfang and CBM , was conducted up to March 2014. A composition of the following MeSH terms and text words was used: ‘TaqIB’ or ‘rs708272’, ‘cholesteryl ester transfer protein’ or ‘CETP’, ‘high density lipoprotein cholesterol’ or ‘HDL-C’ and ‘coronary artery disease’ or ‘myocardial infarction’ or ‘atherosclerosis’. The additional studies were retrieved from the MEDLINE option ‘related articles’ and head searches were also added to the database. We also screened the bibliographies of the original research reports, reviews, and previous meta-analyses to optimize the databank. If the data was deficient or in an inappropriate form, we contacted with the original authors to obtain the raw data.All the studies that aimed for the association of the TaqIB polymorphism with HDL-C levels and CAD risk were potentially included. The following criteria were for the selection: (1) published articles of human-being genetics (full texts or abstracts) without racial or language restrictions; (2) if articles contained more than one geographic or other clinical characteristic subgroup, each subgroup was considered separately; (3) if multiple studies were derived from the same population, only the study with the largest sample size was involved to avoid overlapping data; (4) studies providing sufficient information on the TaqIB genotype by case–control status and/or on circulating HDL-C concentrations across the TaqIB genotype between CAD patients and controls.CAD outcomes were diagnosed according to previous MI, angina pectoris, percutaneous trans luminal coronary angiography, coronary artery bypass grafting or severe angiographic stenosis ( ≥50% of ≥1 major coronary artery) . Acute cA standard data-collection procedure, in line with the inclusion criteria described above was used. Two investigators (Wu and Lou) independently extracted the variables from the individual eligible studies in duplicate and made the characteristics compatible in a pooled database. Any encountered disagreements were resolved by discussion in order to reach a consensus. The following information was extracted from all the eligible studies: first author’s name, publication year, ethnicity, geographic location, study design, population source, endpoints, clinical characteristics of the study subjects , percentage of hypertension, diabetes, smoking status and the distribution of the TaqIB genotype both in patients and controls. The units of circulating lipid profiles were standardized to mmol/L. Continuous variables were expressed as mean ± standard deviation (SD) or median (5th and 95th percentiles). Standard error was converted to SD.http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl). In order to obtain robust evidence of estimating the association between the TaqIB polymorphism and CAD risk, sensitivity analyses were performed by excluding the HWE-deviating studies (P <0.05) [We tested conformity of the TaqIB polymorphism to HWE among controls in each individual study via the chi-square test or Fisher’s exact test, based on a Web program (P <0.05) . We calc2) statistic, ranging from 0 to 100%. A value of 0% indicated homogeneity; by contrast, high values of I2 implied that heterogeneity accounted for most of the between-study variation [Initially, we calculated the summary odd ratios (ORs) of CAD risk and the standard mean difference (SMD) of HDL-C concentrations corresponding to the 95% confidence interval (CI) to assess whether the TaqIB polymorphism was relevant to CAD risk or circulating HDL-C levels or both. Four genetic models, including allele comparison (B2 versus B1), dominant genetic model (B1B2 + B2B2 versus B1B1), recessive genetic model (B2B2 versus B1B2 + B1B1) and homozygote comparison (B2B2 versus B1B1) were used. We utilized a random-effects model based on the DerSimonian & Laird method to evaluate the effect size of each study and to modify the study weights on the basis of the in-study variance. The Mantel-Haenszel model was adopted for checking the possibility of heterogeneity . Uniformariation ,33. The ariation  where P 2 statistic and Egger’s test was regarded as significant [Sensitivity analysis was performed by sequentially removing each individual study to identify those that likely biased the overall estimates. We used the visual funnel plot and Egger’s linear regression test to estimate publication bias. The standard error of log (OR) for each study was plotted against its OR. An asymmetric plot suggests the possible presence of publication bias, which can be verified by a T-test. P <0.05 of the Inificant .Cumulative meta-analysis was used to decipher the impact of the first published study on the subsequent studies and the evolution of the synthesized effects over time was in accordance with the publications ordered by time. Data administration and statistical analysis were conducted by using Review Manager software release 5.0  and Stata 11.0 . All P values were 2-sided.The flowchart depicting the screening process of study selection is shown in Figure Forty-seven studies with 23,928 cases and 27,068 controls were incorporated into the meta-analysis. The allele and genotype frequency of the TaqIB polymorphism is shown in Table 2 = 55.2%, Pheterogeneity <0.0001; dominant model: I2 = 48.6%, Pheterogeneity <0.0001) . In addition, no individual study was shown to substantially influence the overall results.We hypothesized that HWE-deviating studies  might be partly responsible for the striking heterogeneity. Therefore, we performed a sensitivity analysis to compare the summary effects as well as the extent of between-study heterogeneity before and after excluding HWE-deviating studies. However, the summary ORs and the statistical significance of tests did not change substantially after removal of the HWE-deviating studies , but not verified by the Begg-Mazemdar test . Nevertheless, after excluding the HWE-violating studies, the probability of publication bias was diminished and the P value for asymmetry in the funnel plot became non-significant . Further analysis via the trim and fill method suggested that no missing studies were needed to adjust the symmetry in the funnel plot for the TaqIB polymorphism Figure .Figure 3No distinguishable evidence was found that the first published study affected the subsequent replication, as illustrated by the cumulative meta-analysis (data not shown).2 = 67.7%, Pheterogeneity <0.0001) was not observed among Caucasian subjects . Further, the comparison of the B2 allele with the B1 allele yielded a non-significant 8% risk reduction for CAD in the prospective group , which was higher than that in the retrospective group . Upon stratification by population source, the ORs of CAD appeared to decrease in the H-B group  relative to the P-B group . In addition, the risk estimate was less in the MI and ACS groups than in the CAD group . Carrier status for the B2 allele carried a moderate risk reduction of MI  and a suggestive risk reduction of ACS .In view of the considerable heterogeneity in the total analysis, subgroup analysis is an appropriate method to explore the potential sources of heterogeneity. We categorized the data in the light of the different homogeneous characteristics, such as ethnicity, study design, population source and disease type in HWE-confirming studies. The summary estimates for ORs in different subgroups under various genetic contrasts are listed in Table The major environmental exposures were added in a series of univariate models to interpret the potential sources for between-study heterogeneity. Multiple study-level covariates, including average age, BMI, lipid fractions, percentage of male participants, smoking, hypertension and diabetes, were incorporated in our meta-regression. As a result, the CAD risk estimate for the TaqIB polymorphism was significantly influenced by smoking status (P = 0.006) and by circulating HDL-C levels (P = 0.006). This indicates that the correlation of the TaqIB polymorphism with CAD is likely to be strengthened in populations having low smoking rates or low HDL-C levels, with the reduction of CAD risk due to the B2 allele being greater in populations with low smoking rates compared with populations with high smoking rates and in populations with low HDL-C levels compared with populations with high low HDL-C levels Figure .Figure 42 = 0, Pheterogeneity = 0.87)  is determined by the absolute magnitude of its association with the intermediate phenotype (HDL-C in our study). A previous individual patient data-based meta-analysis, including 13,677 Caucasian subjects, provided robust evidence that the TaqIB polymorphism is significantly associated with HDL-C among Caucasians . Hence, To test the reliability and robustness of our data, we did a statistical power analysis as previously described ,69. We a2 = 0, Pheterogeneity =0.52). There seems to be no evidence of publication bias . Utilizing the TaqIB polymorphism as an instrument, we measured the magnitude of the association between increased HDL-C concentrations with CAD under the assumptions required for Mendelian randomization. The Mendelian randomization estimate was computed on the basis of assumed linearity of the association between HDL-C variation and OR for CAD on a log scale [Given the close relationship between the TaqIB polymorphism and HDL-C in these 10 studies of Caucasian subjects, we ascertained that B2 carriers had a decreased risk of CAD by 6% . The results suggest that HDL-C indeed lies on the causal pathway between the CETP TaqIB polymorphism, which modulates HDL-C, to likewise confer the risk of disease. To our best knowledge, the current meta-analysis is one of the largest systematic reviews of studies investigating the relationship between the CETP polymorphism, HDL-C and potential risk of CAD. The synthesized estimation of the TaqIB polymorphism concerning CAD risk was presented in our meta-analysis containing 50,996 subjects. Subsequently, the possible causal inference of HDL-C on CAD risk was further assessed. The overall OR of the TaqIB polymorphism under a random-effects model was suggestive of a modest protective effect on CAD. Considering that violation of HWE might diminish the total effect of the meta-analysis, we performed a sensitivity analysis by excluding the studies demonstrating a departure from HWE. Trends in the ORs did not change substantially by estimation of the association among only the HWE-confirming studies. We provide robust evidence that the TaqIB polymorphism is associated with CAD and that the HWE-violation only slightly influences the interpretations of the observed results in our meta-analysis. Interestingly, the pre-specified subgroup analyses revealed that the B2 allele carriers had a remarkable higher risk reduction in CAD among Asians compared with Caucasians, in spite of similar frequency of the B2 allele. It remains unclear the real reasons for the divergence across the different ethnic groups, because we did not directly test the TaqIB polymorphism in different ethnic groups. We also did not estimate the association between the TaqIB polymorphism and other phenotypes. Given some GWASs have identified that numerous lipid-associated genetic variations differ with ethnicity [Because HDL-C serves an important role in CAD pathogenesis, we expected that the thnicity -74, we ethnicity . Of noteThe strength of the instrument (the TaqIB polymorphism in our study) is determined by the absolute magnitude of its association with the intermediate phenotype (HDL-C in our study). A previous individual patient data-based meta-analysis including 7 large population-based studies and 3 randomized placebo-controlled trials , have provided robust evidence that the TaqIB polymorphism is significantly associated with HDL among Caucasians . Hence, LIPG) and a genetic score containing 14 common single nucleotide polymorphisms (solely concerning HDL-C) as two instruments for Mendelian randomization. As a result, a specific and substantial increase in HDL-C levels due to LIPG Asn396Ser and the genetic score was verified to be not related to MI. Employing various instruments may contribute to the precision of instrumental variable estimates and may facilitate examination of potential instrumental variable assumptions. Besides LIPG, CETP was acknowledged to have a profound influence on HDL-C metabolism and consequently CAD risk. The TaqIB polymorphism, a silent base change affecting the 277th nucleotide, is almost fully concordant with another promoter variants −629 C→A [Mendelian randomization, a form of instrumental variable analysis , was app−629 C→A ,78,79. T−629 C→A , suggest−629 C→A ,81. As a−629 C→A -84. Howe−629 C→A  and a fu−629 C→A .Furthermore, we restate the underlying restriction of raising circulating HDL-C levels as an effective treatment to reduce residual cardiovascular risk in patients treated by conventional statin therapy. Intense research efforts on therapeutic agents have been conducted to reduce the residual cardiovascular risk by raising circulating HDL-C levels. Statins, fibrates and niacin are regarded as effective pharmacological agents for raising HDL-C. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study documented there was no added clinical benefit in using combination therapy with fenofibrate plus simvastatin compared with simvastatin monotherapy, despite the fact there were significantly increased levels of HDL-C in the combination therapy group . In the Another possibility is that the composition of HDL-C is altered in CAD patients and they are no longer productive at high levels or after therapeutic intervention . Some stCommon variants in lipid-associated loci that are also associated with CAD may implicate genes at these loci as possible therapeutic targets. Recently, a large meta-analysis based on GWAS aimed to investigate the genetic markers for blood lipids . A genomThere are still limitations using Mendelian randomization analysis. Potential pleiotropic effects of genes may influence the results when a naturally occurring single nuclear polymorphism is used as an instrument to evaluate disease causality. Although single genetic variation is relative to extensive diseases, many of these associations are false positives because the gene has been more generally characterized than most in population investigations of genetic association studies. Canalization or developmental compensation also provides difficulties in interpreting the gene-disease association. These processes, which bring developmental buffering, offset the influence of the genetic variation or environmental forces , remain In conclusion, our results provided robust evidence that the TaqIB polymorphism, which specifically raised HDL-C concentrations, was uniformly associated with a reduction in CAD risk. However, a lack of causal inference in increased HDL-C levels with the pathogenesis of CAD was detected based on the Mendelian randomization approach among Caucasians. We highlight not only the requirements for further validation of the functional role of HDL-C in reverse cholesterol transport and in the etiology of atherosclerosis, but also as a high possibility that lifestyle interventions or pharmacotherapy, which elevates circulating HDL-C levels, cannot be assumed to benefit CAD patients in reality.Additional file 1: Table S1.The baseline characteristics of all eligible studies in the meta-analysis.Additional file 2:Supplementary material. Study descriptions.


X-ray repair cross-complementing group 1 (XRCC1) gene Arg194Trp polymorphism has been reported to be associated with risk of lung cancer in many published studies. Nevertheless, the research results were inconclusive and conflicting. To reach conclusive results, several meta-analysis studies were conducted by combining results from literature reports through pooling analysis. However, these previous meta-analysis studies were still not consistent. Hence, we used an updated and cumulative meta-analysis to get a more comprehensive and precise result from 25 case–control studies searching through the PubMed database up to September 1, 2013. The meta-analysis was carried out by the Comprehensive Meta-Analysis software and the odds ratio (OR) with 95 % confidence interval (CI) was used to estimate the pooled effect. The result involving 8,876 lung cancer patients and 11,210 controls revealed that XRCC1 Arg194Trp polymorphism was not associated with lung cancer risk . The cumulative meta-analysis showed that the results maintained the same, while the ORs with 95 % CI were more stable with the accumulation of case–control studies. The sensitivity and subgroups analyses showed that the results were robust and not affected by any single study with no publication bias. Relevant studies might not be needed for supporting these results. X-ray repair cross-complementing group 1 (XRCC1) is involved in base excision repair protein that located on chromosome 19q13.2–13.3 with a length of 33 kb . The polIn order to obtain more comprehensive and precise results, we conducted cumulative meta-analysis , 35 to eA study met all of the following inclusion criteria was included: (1) to evaluate the association between XRCC1 Arg194Trp polymorphism and risk of lung cancer; (2) cohort or case–control design and the patients were diagnosed by histology or pathology; (3) the number of genotype distribution in both case and control group were directly reported or calculated from the reported data; and (4) the published language was English or Chinese.The search terms [(“XRCC1” or “X-ray repair cross-complementing group 1”) and “polymorphism” and (“lung cancer” or “lung carcinoma”)] were used to search the PubMed database up to September 1, 2013. The reference list of the included articles and relevant meta-analyses were manually searched.Two authors independently chose 25 case–control studies, which were illustrated in Fig. I2 statistics (I2 ≤ 40 %)  were used to calculate the pooled odds ratio (OR) and its 95 % confidence interval (CI) to present the strength of associations between XRCC1 Arg194Trp polymorphism and risk of lung cancer. The fixed-effects model was used firstly, if heterogeneity among included studies was detected by  ≤ 40 %) , we shifThe influence of sample size on the overall risk estimation was carried out by cumulative meta-analysis , and theThe electronic searching yielded 128 studies, and the hand searching yielded 15 studies initially; finally, 23 articles involving 25 case–control studies  containeI2 ≤ 40 %), and meta-analysis based on fixed-effects model showed that there was no association of XRCC1 Arg194Trp polymorphism with risk of lung cancer .Figure Meta-analysis is a statistical method of combining results across studies from literatures to resolve discrepancy in genetic association studies . The metCompared to previously meta-analyses –33, the Obviously, there were potential to moderate level heterogeneity. From the subgroups analysis, we found that ethnicity and source of control might not be the source of heterogeneity Table . When weThere were some limitations of our meta-analysis. First, there was heterogeneity among included studies. Although the heterogeneity was probably from the study reported by Buch et al. , we coulIn conclusion, this meta-analysis suggests that XRCC1 Arg194Trp polymorphism is not associated with lung cancer risk, either in Asians or Caucasians, either the controls were sourced with or without HWE. These results were not influenced by any single study, and relevant studies are not needed for supporting this result. Due to the limitations of this meta-analysis, current results should be viewed with caution and future studies should be conducted in gene-gene and gene-environment interactions.


Coronary artery disease (CAD) and ischemic stroke (IS) are manifestations of atherosclerosis, with a high death rate. miR-146a is a microRNA that participates in the progress of CAD and IS. A single nucleotide polymorphism (SNP) in the precursor of miR-146a, rs2910164, was found to be associated with the risks of CAD and IS. However, the results were inconsistent and inconclusive. A meta-analysis was performed to assess the relationship of rs2910164 and CAD as well as IS susceptibility. The database Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM) were searched for related studies. Crude odds ratios with 95% confidence intervals were used to investigate the strength of the association by random- or fixed-effect model. A total of eight studies, with 3138 cases and 3097 controls were identified for the meta-analysis. The results shows that rs2910164 is associated with the risk of CAD significantly in allelic model (OR = 0.86), homozygous model (OR = 0.70), heterozygous model (OR = 0.80) and dominant model (OR = 0.76). The subjects carrying the GG genotype, GG + GC genotype or G allele are at lower risks of CAD. For the susceptibility of IS, there are no significant associations between rs2910164 and total studies. However, in subgroup analysis by sample size and ethnicity, the GG, GG + GC and G allele of rs2910164 are found to be associated with higher risks of IS in large sample size group and in Koreans, under homozygous and dominant models. In conclusion, the current meta-analysis suggests lower risks of CAD for GG, GG + GC genotype and G allele of rs2910164, while rs2910164 is not associated with the risk of IS. Thus rs2910164 might be recommended as a predictor for susceptibility of CAD, but not IS. Cardiovascular diseases are the major cause of death and disability worldwide. According to the World Health Organization report in 2011, more than 17 million people died of cardiovascular diseases. Coronary artery disease (CAD) is characterized by occlusive epicardial coronary artery stenosis. Ischemic stroke (IS) is a major kind of stroke, which causes a high death rate and adult disability in the world. According to the report of Liu, the annual stroke mortality rate was 120–180 per 100,000 in China ,4.MicroRNAs are small, non-coding RNAs which regulate the gene expression in post-transcriptional levels. The regulation effects of microRNAs are obtained by binding to the 3ʹ-UTR of target mRNAs, and lead to degradation or translation repression of target genes. Previous reports predicted that 1/3 of human genes were regulated by microRNAs . Thus, tmiR-146a is a microRNA located at the human chromosome 5q33. Previous studies have demonstrated that miR-146a participates in inflammatory processes, thus interferes with the pathology of cardiovascular diseases . StudiesThus it is necessary to make a precise and comprehensive estimation of the association between miR-146a and the risks of CAD and IS. In the present study, eight studies, including 3138 cases and 3097 controls, were included in the meta-analysis.A total of 19 studies were obtained from the literature search after duplicates were removed. Among them, three studies were excluded for irrelevance, two for being reviews, three for being master degree theses and three were only abstracts. Finally, eight studies meeting the criteria were preserved, which included 3138 cases and 3097 controls. The Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow chart is shown in The results of meta-analysis for the association between miR-146a (rs2910164) and CAD, IS risks were shown in p = 0.01), homozygous model , heterozygous model  and dominant model . When we conducted a subgroup analysis by sample size and ethnicity, the same significant associations were observed in the large sample size group and the Chinese group. However, in the small sample size group, a significant decrease in CAD risks was only found in the homozygous model.For CAD, significantly decreased risks were found to be associated with rs2910164 under all genetic models, allelic model  (data not shown). For CAD, there are no significant heterogeneity existing among all studies.For IS, the subgroup analysis indicated the sample size was the source of the heterogeneity among studies , homozygous model (OR = 0.70), heterozygous model (OR = 0.80) and dominant model (OR = 0.76). The subjects carrying GG genotype, GG + GC genotype or G allele are at lower risks of CAD. For the susceptibility of IS, there are no significant associations between rs2910164 and total studies. However, in subgroup analysis by sample size and ethnicity, the GG, GG + GC and G allele of rs2910164 are found to be associated with higher risks of IS in large size group and in Koreans, under homozygous and dominant model.et al. [et al.’s in CAD. Although we found a similar lower CAD risks for G allele vs. C allele, our meta-analysis also demonstrated a lower risks of CAD for GG/GC and GG genotype vs. CC carriers  and TNF receptor-associated factor 6 (TRAF-6). IRAK-1 and TRAF-6 are upstream regulators of NF-κB activation, and major signal transducers of the Toll-like receptor (TLR) system . The SNPThe results of the present meta-analysis should be interpreted carefully because of the following limitations. Firstly, the number of patients was relatively small, and may influence the outcomes. After a very comprehensive literature search from several different databases, only a total of eight studies were included in the present meta-analysis. Among them, four are related to CAD (1265 cases and 1241 controls) and four are related to IS (1873 cases and 1856 controls). The overall OR only indicated the associations between rs2910164 and CAD. However, no associations were found between rs2910164 and IS risk. The second limitation is that the clinicopathological characteristics or disease subtypes are limited in most of these studies. Although we conducted subgroup analysis by clinicopathological characteristics in IS, only half of the included studies provide the necessary data. And for CAD, no such characteristics were available. Thirdly, CAD and IS are both multi-factorial diseases influenced by both genetic and environmental factors. The gene-gene and gene-environment interactions may play important roles in the function of rs2910164, but most studies lack information about environmental exposure and multiple SNPs in miRNA-encoding genes. The fourth limitation lies in the ethnicity of the subjects. Most of the patients were Asians in the present study and this limited the general application of the results to other populations.In conclusion, the current meta-analysis suggests a decreased risk of CAD for GG, GG + GC genotype and G allele of rs2910164, while rs2910164 is not associated with the risk of IS. Thus rs2910164 might be recommended as a predictor for susceptibility of CAD, but not IS. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity among study designs. Further study is needed to evaluate the association of rs2910164 and these two diseases, especially in a large sample size, in Caucasians, and with clinicopathological characteristics.Published studies were systematically searched by Mei-hua Bao and Yan Xiao; the electronic databases Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Literature Database (CBM) were searched for the following terms: “Coronary artery disease (CAD)” or “ischemic stroke (IS)” and (“miR-146a” or “miRNA-146a” or “microRNA-146a”) and (“polymorphism” or “mutation” or “variant” or “SNP” or “single nucleotide polymorphism”), without restriction on language. The deadline for publication was 15 March, 2015. All the results from the databases were screened. First, we screened the title. If the titles fulfilled our criteria, we then screened the abstract. We retrieved the full text if the abstract was interesting. All eligible studies were retrieved manually for other potentially relevant studies from their references. We contacted the authors for related data when they were unavailable in the original publications.Inclusion Criteria: (a) Case-control design; (b) The association of miR-146a (rs2910164) and CAD or IS risks should be evaluated; (c) The genotype in the control group should be agreed with the Hardy-Weinberg equilibrium (HWE); (d) The data in the publication are sufficient for present estimation. Studies were excluded if any of the following applies: (1) Repeat publications, abstracts, letters or reviews; (2) Studies not meeting all of the inclusion criteria.We extracted the information from each eligible publication manually by two investigators independently (Qing-song Zhang and Ji Luo). For each study, the extracted information included: First authors’s name, year of publication, country, ethnicity, genotype method, sex ratio, age, source of controls, diseases, genotype numbers of cases and controls. If we encountered discrepancies during data extraction, it was resolved by a consensus achieved by the third author (Jian-ming Li).The quality of the included studies was evaluated by the following aspects: source of cases, source of controls, specimens used for determining genotypes, total sample size and evidence of HWE. The quality scores ranged from 0–15, higher scores indicating better quality . The qua2-test was used to evaluate the HWE of the control group polymorphism. If p < 0.05, it was considered to be deviated from HWE. To evaluate the association between miR-146a (rs2910164) and disease (CAD and IS) risk, the crude odds ratio (OR) with 95% confidence interval (CI) was used. The pooled ORs were calculated using genetic model of allelic model (G vs. C), homozygous (GG vs. CC), heterozygous (GC vs. CC) and dominant (GG/GC vs. CC) model, and the statistical significance was determined by the Z-test, and p < 0.05 was considered to be statistically significant. Subgroup analysis was conducted according to the sample size. Total samples less than 1000 was treated as small, and otherwise as large.χI-square statistical test, which was not dependent on the number of studies in the meta-analysis [I2 > 50%), the random-effects model (the DerSimonian and Laird method) was used for the meta-analysis [p < 0.05 was considered to be statistically significant [The statistical heterogeneity between studies was evaluated by analysis . If theranalysis . Otherwianalysis . Sensitinificant . All sta


Aims. Published data on the associations of VEGF polymorphisms with diabetic retinopathy (DR) susceptibility are inconclusive. A systematic meta-analysis was undertaken to clarify this topic. Methods. Data were collected from the following electronic databases: PubMed, Embase, OVID, Web of Science, Elsevier Science Direct, Excerpta Medica Database (EMBASE), and Cochrane Library with the last report up to January 10, 2014. ORs and 95% CIs were calculated for VEGF–2578C/A (rs699947), –1154G/A (rs1570360), –460T/C (rs833061), −634G>C (rs2010963), and +936C/T (rs3025039) in at least two published studies. Meta-analysis was performed in a fixed/random effect model by using the software STATA 12.0. Results. A total of 11 studies fulfilling the inclusion criteria were included in this meta-analysis. A significant relationship between VEGF+936C/T (rs3025039) polymorphism and DR was found in a recessive model  = 0.01) in Asian and overall populations, while a significant association was also found between –460T/C (rs833061) polymorphism and DR risk under a recessive model  = 0.02). Conclusions. Our meta-analysis demonstrates that +936C/T (rs3025039) is likely to be associated with susceptibility to DR in Asian populations, and the recessive model of –460T/C (rs833061) is associated with elevated DR susceptibility. Type 2 diabetes (T2DM) is a metabolic disorder that has caused major public health threat throughout the world. Diabetic retinopathy (DR), one of the most prominent pathological microvascular complications of T2DM, is also the leading cause of legal blindness in working-age adults , but itsHyperglycemia has been regarded as the dominant pathogenic factor in the development and progression of DR . The WisCurrently, the pathogenesis of DR is considered to be influenced by environmental and genetic factors. Ethnic differences in the prevalence of DR may offer understandings into the relative importance of genetic or environmental risk factors. Therefore, it is important to identify molecular markers that may help in the diagnosis of DR in multiple populations.Diabetic retinopathy is characterized by vascular permeability, increased tissue ischemia, and angiogenesis. Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor , plays aThe human VEGF gene is located on chromosome 6 (6p21.3) and highly polymorphic, especially in the promoter, the 5′-untranslated (UTR) and the 3′-untranslated region. The promoter has a single transcription start site near to a group of Sp1 binding sites and covers AP-1 and AP-2 binding sites , while tUntil now, the exact pathogenesis of DR is not yet fully clarified, despite a large number of studies on the candidate genes for the DR susceptibility in subjects of various ethnicities; however, most of the data appear to be inconclusive and require further confirmation. This may be attributed to the limited sample size and inadequate statistical power and studies with a relatively small sample size, which may have affected their reliability. Meta-analysis provides the most accurate estimate of the nature and magnitude of an effect by combining the results of multiple independent studies and has the ability to reduce the potential influence of types I and II errors that appear within individual studies . TherefoA systematic literature search in PubMed, Embase, OVID, Web of Science, Elsevier Science Direct, Excerpta Medica Database (EMBASE), and Cochrane Library  was carried out to identify studies involving the associations between DR and the above mentioned VEGF polymorphisms. The language was limited to English. In this meta-analysis, the controls were patients with T2DM without DR (DWR) and the cases were T2DM patients with DR . We conducted subgroup analyses stratified by status of DR (based on the studies that had defined cases solely in the presence of PDR or NPDR) .The search terms were as follows: “vascular endothelial growth factor or VEGF” in integration with “polymorphism or mutation or variant” and in integration with “diabetic retinopathy or DR or NPDR or PDR” to identify all publications, which investigated the associations of the VEGF polymorphisms with DR risk in all ethnic populations. Meanwhile, we also searched the reference lists of included studies to identify other potentially eligible studies. Case reports, editorials, and reviews were excluded.Studies included in our meta-analysis must meet the following criteria: (1) the article pertained to the above mentioned VEGF polymorphisms and DR risk; (2) sufficient data for examining odds ratios (ORs) with 95% confidence intervals (CIs); (3) genotype distributions of polymorphism of the control population were consistent with Hardy-Weinberg equilibrium (HWE).Two investigators independently extracted data. From each study, we extracted the first author's name, year of publication, country of origin, ethnicity of samples, number of cases and controls, and the available genotype frequency of the polymorphisms. Ethnicity was classified as White or Asian. The control group sources were classified as population-based or hospital-based controls. The deviation of the genotype frequencies in the control population from HWE was calculated separately for each study.P < 0.05 was considered statistically significant.We conducted the meta-analysis using STATA software . ORs and 95% CIs were calculated to assess the strength of the associations between the VEGF polymorphisms and DR susceptibility. The pooled OR was calculated for the codominant model, dominant model, recessive model, and additive model, respectively. I2, was calculated to identify the heterogeneity [I2 < 50%). Alternatively, the random effects model was used (I2 > 50%). If there is heterogeneity, the Galbraith graph was used to explore the potential sources of heterogeneity. We assessed the potential publication bias with funnel plots of the effect sizes versus the standard errors and identified the significant asymmetry by the Begg's test [The inconsistency index, ogeneity . The datg's test . To testg's test . The leag's test .The initial search yielded 259 references. Based on titles and/or abstracts, we excluded 202 and reviewed 57 full-text reports. Applying the study inclusion criteria, 11 studies were included in this meta-analysis . The stuSeven relevant studies with a total number of 1,085 cases and 1,019 controls were included in −634G>C rs2010963) analysis –23; 6 re10963 anaOf the 11 studies, 9 were hospital-based control studies –25, 27, Three relevant studies were included in −634G>C (rs2010963) analysis (PDR versus NPDR), and 3 relevant studies were included in +936C/T (rs3025039) analysis (PDR versus NPDR) .Analyses were performed for all cases with any form of DR compared with all diabetics without retinopathy (DWR). The summary results of meta-analysis for VEGF gene polymorphisms and DR risk were shown in Our meta-analysis did not show any significant correlations between −2578C/A (rs699947) and DR risk in hospital-based control studies, overall populations, and Asians populations, respectively .P(z) = 0.01). The effects of the ORs and 95 CIs of the Asian populations and overall populations were the same, because all of the studies included in the +936C/T (rs3025039) were all Asian populations (Our data demonstrated that +936C/T (rs3025039) polymorphism increased the DR risk in the Asian populations  = 0.02) (A significant association between the −460T/C (rs833061) polymorphism and increased DR risk was detected under a recessive model  .There were only two studies included in the −1154G/A (rs1570360) meta-analysis; therefore the −1154G/A (rs1570360) was not further analyzed.There were only three studies included in −634G>C (rs2010963) and +936C/T (rs3025039) meta-analysis (PDR versus NPDR) . Our metIn P = 0.53 for the recessive model of +936C/T (rs3025039) in Asian populations; P = 0.66 for the recessive model of −460T/C (rs833061)) ) .Begg's test and Egger's test did not detect any significantly statistical evidence of publication bias for any of the genetic models. This indicates that the results of this meta-analysis are relatively stable and that publication bias is unlikely to have affected the results.We performed the sensitivity analyses by sequentially removing individual eligible study. The results indicated that the overall significance of the ORs was not altered by any single study for the recessive model of the +936C/T (rs3025039) polymorphism in Asian populations and −460T/C (rs833061) (data not shown). The sensitivity analyses also indicate that results of our study are stable and reliable.To our best of knowledge, this is the first meta-analysis involving the five VEGF polymorphisms at the same time. Our meta-analysis finds significant associations between +936C/T rs3025039) and DR susceptibility in Asian populations, while Kim et al. found that +936C/T (rs3025039) polymorphism was related with DR in Korean populations ; however039 and DThe most investigated VEGF polymorphism has been −634G>C (rs2010963), with most studies showing no significant association between this polymorphism and the presence of DR; as well, the present meta-analysis confirms the nonsignificant association across all of the overall and subgroup analysis, which is consistent with the results of T. Zhao and J. Zhao meta-analysis . AlthougContrary to our meta-analysis, Qiu et al. conducted a similar meta-analysis only on −634G>C polymorphism and DR, which involved a total of 1525 DR cases and 1422 DWR controls in 9 independent studies, they observed a significant relationship between −634G>C (rs2010963) polymorphism and DR in an allelic genetic model (OR: 1.13) and a recessive genetic model (OR: 1.26). However, the genotypes deviation of the controls in Yang et al.'s study was not consistent with HWE  but was Some possible limitations of our meta-analysis should be taken into consideration. First, the conclusion was based on a relatively small number of participants. Second, potential publication biases may exist in this meta-analysis because studies excluded the non-English-language publications. Third, this meta-analysis was based on unadjusted data due to a lack of detailed genotype information stratified by many variables  in original articles, and a more precise analysis would have been performed if all individual raw data had been available.In spite of these potential limitations, our meta-analysis has some strength. First, we sought to find as many publications as we could by searching various databases. The sufficient number of cases and controls were pooled from multiple studies, which apparently increased the statistical power of our analysis. Second, in order to minimize the potential bias, we designed a rigorous protocol and utilized explicit methods for the literature search, study selection, data extraction, and statistical analysis. The symmetry of the funnel plot suggests that bias is less likely to have appeared, indicating that the pooled results of our analysis may be unbiased. Third, no publication bias was detected among the pooled results. Last, we considered not only association between the most investigated −634G>C (rs2010963) and DR susceptibility but also paid attention to the impact of other VEGF polymorphisms −2578C/A (rs699947), −1154G/A (rs1570360), −460T/C (rs833061), and +936C/T (rs3025039). We could therefore give a more complete picture on the role of VEGF polymorphisms contributing to DR risk.In conclusion, our meta-analysis revealed some significant associations between VEGF polymorphisms and DR susceptibility. However due to the relatively small sample size in this meta-analysis, in order to reach a more definitive conclusion, further studies based on larger sample size and substantiation of the variations through functional studies are still needed.


TLR) polymorphisms and tuberculosis susceptibility have yielded varying and often contradictory results in different ethnic groups. A meta-analysis was conducted to investigate the relationship between TLR variants and susceptibility to tuberculosis, both across and within specific ethnic groups.Studies investigating the influence of toll-like receptor (An extensive database search was performed for studies investigating the relationship between TLR and tuberculosis (TB) susceptibility. Data was subsequently extracted from included studies and statistically analysed.TLR polymorphisms. Various genetic models were employed. An increased risk of TB was found for individuals with the TLR2 rs3804100 CC and the TLR9 rs352139 GA and GG genotypes, while decreased risk was identified for those with the AG genotype of TLR1 rs4833095. The T allele of TLR6 rs5743810 conferred protection across all ethnic groups. TLR2 rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group. The T allele of TLR4 rs4986791 was also found to increase the risk of TB in the Asian subgroup. All other TLR gene variants investigated were not found to be associated with TB in this meta-analysis.32 articles involving 18907 individuals were included in this meta-analysis, and data was extracted for 14 TLR variants showed no significant association with TB, indicating that additional studies investigating a wider range of pattern recognition receptors is required to gain a better understanding of this complex disease.Although general associations were identified, most  Mycobacterium tuberculosis (M. tuberculosis), is the leading cause of death attributable to a single infectious agent worldwide [M. tuberculosis and activation of the adaptive immune response [Tuberculosis (TB), caused by orldwide . The hosresponse . This prresponse . These Presponse . For theresponse  and are As the PRR encoding genes play an important role in host immunity, variants in these genes could lead to structural and functional changes in these receptors causing an altered immune response, and influence TB disease progression .TLR2 SNPs have been conducted, often with varying and even contradictory results in different ethnic groups. The A allele of the TLR2 rs11938228 polymorphism has been associated with TB disease  in European and Asian populations, but not African [TLR4 polymorphisms. TLR4 recognises mycobacterial lipopolysaccharides (LPS) and can trigger one of two innate immune response pathways, the MyD88 dependant or independent pathway. Impairments in this PRRs signalling capability can greatly influence TB disease susceptibility [TLR4 rs4986790 and rs4986791 are two of the most extensively investigated and were shown to be associated with TB susceptibility, for the allelic and heterozygous model, in one Asian population [TLR2 and 4 are the most studied TLRs with regards to TB disease. TLR2 forms heterodimers with either TLR1 or TLR6, resulting in the recognition of a wide range of mycobacterial PAMPs, including tri and diacyl lipopeptides  and pept African  or Hispatibility . TLR4 rspulation . While sTLR1, 2, 4, 6, 8, and 9 SNPs, to assess their association with TB susceptibility both across and within different ethnicities. We show that most of the commonly investigated SNPs have no association with TB disease susceptibility across ethnic groups. Subgroup analysis was possible for eight SNPs and two of these were significant in our analysis. Four SNPs  were associated with TB susceptibility across ethnic groups, while subgroup analysis on TLR2 rs5743708 and TLR4 rs4986791 showed significant association in the Asian and Hispanic ethnic groups. Further investigation to validate these findings will be required as more studies from various ethnic groups become available.Meta-analysis enables us to systematically review the results of previous studies to derive a relevant, objective and unbiased conclusion by taking into account the totality of evidence on a specific subject . By consTLR genes and susceptibility to TB was conducted, by two researchers (HS and MS), using the PubMed, Medline and EMBASE databases, including studies up to 31 May 2015. The search strategy was based on various combinations of the following terms: “TLR”, “toll-like” or “toll like” in combination with “tuberculosis”, “TB”, “M.tb” or “mycobacteria” and in conjunction with “genotype”, “allele”, “polymorphism” or “variant”. Furthermore, the reference lists of the publications identified were searched for further relevant studies. If data was missing the corresponding author of the study was contacted via e-mail to obtain missing data where possible.A systematic search of articles relating to variants in TLR variants and TB or pulmonary TB (pTB) susceptibility; (3) genotype frequencies for both cases and controls; (4) Newcastle Ottawa Scale (NOS) quality score of ≥6 [M. tuberculosis; (2) review articles or previous meta-analyses; (3) insufficient or duplicate data; (4) not in English.The following criteria were required for inclusion of studies: (1) case-control study; (2) evaluation of re of ≥6 . StudiesFor all eligible studies the following data was extracted from the original publications: title, first author and year of publication, ethnicity of study population, number of cases and controls, and genotype frequencies for cases and controls. The data extraction was done independently by HS and MS and then compared to detect any discrepancies.http://www.r-project.org/). Hardy-Weinberg Equilibrium (HWE) was calculated for the control group of each study using the Chi-square test in the HardyWeinberg package v1.4.1 (http://cran.r-project.org/). Odds ratios (OR) and 95% confidence intervals (CI) for each study and the pooled result was calculated to assess the association between TLR variants and TB susceptibility. The allelic model (2 vs. 1), homozygote comparison (22 vs. 11), heterozygote comparison (12 vs. 11), dominant model (22 + 12 vs. 11) and recessive model (22 vs. 12 + 11) was analysed for each SNP (if data from three or more studies were available) using the metafor package v1.6–0 (http://cran.r-project.org/). Analysis was also performed by ethnicity  if at least three articles for a specific ethnicity was available. The Chi-squared based Q statistic and I2 test was used to assess the heterogeneity between included studies [p-value > 0.1 the fixed effects (FE) model (inverse-variance method) was implemented and for p-value ≤ 0.1 the random effects (RE) model (restricted maximum likelihood estimator) was used to calculate pooled OR and CI values [p-value <0.05 was considered significant. Genotypes that displayed deviations from HWE or studies that had a low NOS score were excluded from this meta-analysis. Due to these exclusions sensitivity analysis was not strictly necessary, but was performed to ensure stability of the meta-analysis, based on the I2 statistic. Confounding factors  were not included in the analysis as this information was not available for all included studies. Finally, publication bias was assessed using Egger’s weighted regression test with inverse sample size estimator, as this gives a better estimate of bias than the more commonly used standard error estimator if the number of studies included are limited [p-value < 0.05 was taken to indicate the presence of publication bias, but was only considered valid if more than five studies were included. Any bias was corrected for using the Duval and Tweedie trim and fill method [Analysis of the extracted data was performed using the freely available R programming environment v3.1.2 , resulting in 32 articles  were also considered, but no GWAS study found an association between TLR polymorphisms and TB susceptibility and data was not available for the SNPs analysed in this meta-analysis.The search using PubMed, Medline and EMBASE databases yielded 351 articles . Of thesarticles  being anTLR1 rs5743618 [TLR2 rs3804099 [TLR4 rs4986790 [TLR6 rs5743810 [TLR9 rs1870884 [TLR8 SNPs rs3764879 [TLR SNPs. A summary of the meta-analysis as well as Egger’s test for publication bias results can be found in the We analysed 14 SNPs in this meta-analysis, of which eight  hs3764879 ,42 and rs3764879 –44 are lTLR1 rs4833095 SNP using the FE model given that minimal heterogeneity existed between the studies. The heterozygous comparison showed decreased susceptibility to TB for individuals with the AG genotype . The dominant model also showed a decreased susceptibility to TB with the AA plus AG genotype  indicating that the AG genotype might exert a protective effect  and Hispanic group . Three studies were included for each ethnic group and statistical analysis was done using the FE model. In the Asian population the A allele increased susceptibility to TB , while iLittle heterogeneity existed between the 7 studies included in the meta-analysis of this SNP and thus the FE model was used to analyse the homozygote and recessive models, both of which indicated that the CC genotype increases the risk of developing TB  .Nine studies were included in the meta-analysis of this SNP, but no significant association with TB susceptibility was found overall. In the subgroup analysis of the Asian population, which included 4 studies, the T allele, TC and TT genotypes were associated with increased susceptibility to TB in the allelic, heterozygous and dominant models, all of which were analysed using the FE model as very little heterogeneity was observed  .The 4 articles included for the meta-analysis of this SNP showed no significant heterogeneity. The T allele conferred protection against TB in the allelic model  and the TT and TC genotypes also had a protective effect against TB infection in the homozygote, heterozygote, dominant and recessive models  . SubgrouFour studies were included in the analysis of this SNP. The GA and GG genotypes for the heterozygous and dominant comparison were associated with increased susceptibility to TB when analysed using the FE and RE models, respectively  .TLR1 rs5743618 and its subgroup analysis on the Asian population showed publication bias for the allelic, heterozygote and dominant model. However, correcting for this bias did not change the significance of the results  of each model for each SNP. However, the pooled results did not significantly differ for any SNP regardless of the statistical model used.TLR SNPs in order to increase the sample size and in turn the power to find or disprove previous associations. Furthermore, meta-analysis gives an indication of which TLR SNPs are associated with TB susceptibility across ethnicities and which are specific to a certain ethnic group. For this meta-analysis 14 of the most commonly investigated TLR SNPs were analysed of which five were associated with TB disease susceptibility across different ethnic groups. Seven of the 14 analysed SNPs had enough data available for subgroup analysis of which two showed associations in subgroup analysis but not across different ethnic groups.The influence of TLRs on TB susceptibility has been extensively investigated and while often associated, replication in different ethnic groups has yielded contradictory results . One facTLR1 rs4833095 was associated with resistance to TB across ethnic groups in this meta-analysis. This non-synonymous polymorphism, located in the extracellular domain, results in an asparagine to serine amino acid change [TLR1 rs4833095 is in strong linkage disequilibrium (LD) with TLR1 rs5743618 and determining how these two SNPs contribute to TB susceptibility has proven difficult. Studies in HEK293 cells have shown that the GG genotype of rs5743618 resulted in decreased NF-kB expression, while the presence of any of the rs4833095 alleles did not further affect NF-kB levels [et al. [The AG genotype of d change . This amd change . TLR1 rsB levels . UciechoTLR1 rs4833095, but Zhang et al. [TLR1 rs5743618 and also found no association with TB susceptibility, which corresponds with our results. Our study had greater power to detect associations due to an increased sample size (2769 cases and 2625 controls vs. 1648 cases and 1216 controls).The AG  and AA  genotypeg et al.  conducteTLR2 rs5743708 across populations no association with TB susceptibility was found, but in the subgroup analysis of the Asian and Hispanic populations the AA and AG genotypes were significantly associated with TB disease susceptibility, as found previously [M. tuberculosis proliferation as well as stimulating the migration of immune cells to the site of infection. Furthermore, TLR2 has been shown to form heterodimers with TLR1 and TLR6 to recognise a wide variety of ligands [In the meta-analysis of eviously , 27. Thieviously , and stueviously . TNFα aneviously . These R ligands  and thusTLR2 rs5743708 yielding similar results. Sun et al. [et al. [et al. [Three meta-analyses have previously been done on n et al.  found th [et al.  found thTLR2 rs3804100, which represents a synonymous serine to serine amino acid substitution at position 450 in the extracellular domain of TLR2, has to date not been fully investigated and the functional effects of this SNP are still uncertain. The CC genotype of this polymorphism is associated with latent TB infection but not with active pTB disease [et al. [et al. [et al. [ disease , is asso disease . This co [et al.  had a smTLR4 rs4986791, but subgroup analysis in the Asian population showed increased susceptibility to TB. This missense variant results in an amino acid substitution of threonine with isoleucine in the extracellular domain of TLR4 and is thought to alter a co-receptor binding region affecting the ability of the receptor to induce signalling in response to LPS stimulation in some cell types [There was no global association with TB susceptibility observed for ll types . Previoull types ,27, whicll types ,52.TLR6 rs5743810 SNP is that the T allele, and the TC and TT genotypes have a protective effect against TB development. This non-synonymous polymorphism results in an amino acid change from proline to serine in the extracellular domain and has been proposed to influence ligand recognition and reduced signal response [et al. [et al. [M. tuberculosis. These functional studies correlate with the results found in this meta-analysis as well as that of Zhang et al. [The overall trend for the response . The T a [et al.  to reduc [et al.  showed tet al. [TLR9 gene, or is in LD with a polymorphic regulatory region that controls TLR9 expression. A second hypothesis is that this intronic variant could introduce alternative splice sites, affecting the TLR9 mRNA transcript and thus the structure and signalling capability of this PRR, leading to an altered immune response [TLR9 rs352139 polymorphism might influence TB susceptibility, coinciding with previous results [The intracellular TLR9 molecule recognises unmethylated CpG motifs in mycobacterial DNA  and in Tet al.  proposedresponse . The res results , 57, 58.TLR SNPs identified in this meta-analysis have not been fully investigated. Given that the majority of these SNPs result in structural changes (non-synonymous or splice-site variants) it could cause altered PRR signalling and efficacy. Impaired signal transduction could lead to reduction of activated transcription factors (e.g. NF-kB) and thus altered levels of pro and anti-inflammatory cytokines, nitric oxide, chemokines and interferon (IFN) inducible genes [The functional effects for most of the associated le genes . An effele genes .TLR polymorphisms on disease susceptibility seem to be population dependent. This lack of association across ethnic groups may be due to the large variability in allelic distribution between ethnic groups, which may in part be explained by evolutionary pressures. In Europe, the epidemic proportions of TB during the industrial revolution could have led to natural selection and thus the accumulation of SNPs that protected against TB. Conversely, the African populations encountered high levels of TB only at a much later stage and would have had less time to accumulate protective polymorphisms [TLR2 rs5743708 the minor allele was present in the Asian ethnic group only in cases (MAF = 0.03), while in the Hispanic ethnic group the minor allele was present only in controls (MAF = 0.015). This could have led to the opposite effect detected for TB susceptibility in these two ethnic groups. In the 1000 genomes project [TLR2 rs5743708, as was observed for monocyte chemoattractant protein–1 (MCP–1) gene polymorphisms [TLR4 rs4986791 the Asian population was the only ethnic group that showed a significant difference between cases (MAF = 0.125) and controls (MAF = 0.09)  . However = 0.09) . FurtherM. tuberculosis and protection against TB that were not investigated in this meta-analysis, which could also have gene-gene interaction effects that were not possible to investigate here. Finally data on confounding factors such as age, gender and smoking, which may differ between cases and controls and between studies, was mostly not available and thus could not be corrected for using meta-regression analysis. These confounding effects could generate false findings (positive confounding) or obscure true associations (negative confounding) and could thus influence the results [The lack of associations across ethnic groups could be due to the limitations of this meta-analysis. Firstly, the number of studies available that investigate the association between TLRs and TB susceptibility is limited. The majority of SNPs investigated have only one or two studies and as one of the inclusion criteria was that at least three studies be available for the meta-analysis, a large number of variants could not be investigated. The lack of studies also meant that for many of the SNPs investigated even the pooled sample size was limited, lowering the power to find an association, especially for subgroup analysis. Furthermore, there are many more types of PRRs  that are involved in the recognition of  results .M. tuberculosis infection if it is either excessive or inadequate [M. tuberculosis infection.Obtaining across or within ethnicity-specific information about the effect on TB susceptibility due to genetic variations in the innate immune system could have valuable applications in “host-directed therapies”  or transadequate , a deepeM. tuberculosis, other PRRs and gene-gene interactions should also be investigated. There is a measure of redundancy in the immune system as one type of PAMP can trigger multiple PRRs and lead to the activation of similar immune pathways. Additional studies with larger sample sizes and ethnic variety should be conducted on all PRRs involved in M. tuberculosis detection to shed some light on this complex disease and for the data to be usable in the medical field.Given the lack of association between TLR and TB, it is clear that although TLRs may be critical for the defence against Results from GWAS investigating TB susceptibility do not coincide with results from this and other meta-analysis –72. ThisTLR SNPs in relation to TB susceptibility. We found that the majority of SNPs showed no association in general or in ethnic subgroup analysis. Only four SNPs  showed significant general associations and two others showed significant subgroup associations (rs5743708 and rs4986791). While this meta-analysis gives an overview of the effect of TLR SNPs on TB disease susceptibility, more studies in various ethnic groups need to be done in order to reinforce the results of this meta-analysis and fully elucidate which variants are population-specific and which have a general association with TB susceptibility.In summary, this meta-analysis aimed to summarize the effects of the most commonly investigated S1 FigA) Allelic model, Ai) Allelic model following D&T correction, B) Homozygote comparison, C) Heterozygote comparison, Ci) Heterozygote comparison following D&T correction, D) Dominant model, Di) Dominant model following D&T correction, E) Recessive model. OR: odds ratio; 95%CI: 95% confidence interval; D&T: Duval and Tweedie.(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S1 FileComplete R-script for the meta-analysis of all models, plots, publication bias and sensitivity analysis.(R)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.


The beta2-adrenergic receptor (ADRB2) gene polymorphism has been implicated in susceptibility to obesity, but study results are still controversial.The present meta-analysis is performed to determine whether there are any associations between the Gln27Glu (rs1042714) or the Arg16Gly (rs1042713) polymorphisms in ADRB2 and obesity susceptibility.The PubMed (1950–2014), Embase (1974–2014), and China National Knowledge Infrastructure  databases were searched using the search terms , “polymorphism,” and “obesity”. Fixed- or random-effects pooled measures were determined on the bias of heterogeneity tests across studies. Publication bias was examined by Egger's test and the modified Begg's test.I2 = 49%, P = 0.009) and the dominant model , whereas no significant association was found in the other models for rs1042714. Also, no significant association was found between the rs1042713 (Arg16Gly) gene polymorphism and the risk of obesity in all genetic models. In addition, neither rs1042713 (Arg16Gly) nor rs1042714 (Gln27Glu) showed any significant association with obesity susceptibility when the population were stratified based on gender.Eighteen published articles were selected for meta-analysis. Overall analyses showed that rs1042714 (Gln27Glu) was associated with significantly increased obesity risk in the heterozygote model  polymorphism is associated with obesity susceptibility. However, our results do not support an association between rs1042713 (Arg16Gly) polymorphisms and obesity in the populations investigated. This conclusion warrants confirmation by more case-control and cohort studies. Compelling evidence demonstrates that both obesity and other related traits have a significant genetic component A number of polymorphisms have been well-studied in ADRB2 and obesity. However, individual reports regarding ADRB2 polymorphisms with obesity have produced inconsistent results. For example, a previous study including 4,193 Japanese subjects indicated that rs1042713 was not a major contributing factor for obesity in Japanese men The first report of significance of ADRB2 was published in 1954 To be included in the meta-analysis, the identified articles had to meet all the following criteria: a) evaluation of Gln27Glu (rs1042714) or Arg16Gly (rs1042713) polymorphism and obesity, b) inclusion of quantitative information on the estimated risk of ADRB2 Gln27Glu (rs1042714) and/or Arg16Gly (rs1042713) polymorphism for obesity, and c) inclusion of complete information about all genotype frequencies, d) used a case control or cohort or cross sectional design, randomization or blinding is not necessary; The exclusion criteria were as follows: a) papers not related to ARDB2 polymorphism and obesity research, b) review articles, commentaries, or unpublished reports, c) papers without usable data, and d) duplicate publications.We followed the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines for reporting meta-analysis of observational studies Some authors provided data only on subjects of one gender, some authors gave information on subjects of each gender, while others failed to report gender at all (gender not identified). The latter studies were included only in the group of both genders combined. Then we calculated the Hardy-Weinberg equilibrium for every study, both in the main group and in the gender-based subgroups. Eventually, 18 publications were enrolled in the main analyses, including 15 case control studies, one random study, one cross sectional study and one cohort study. Using these genotype comparisons, we pooled together the populations of both genders from all studies, and performed gender-based subgroup analyses that included all suitable studies. Nine publications were included for the ADRB2 Arg16Gly (rs1042713) gender-based groups and 17 publications were enrolled for the Gln27Glu (rs1042714) gender-based groups.Summary statistics were estimated in Review Manager 5.1 software . The association between the rs1042714 gene polymorphism and obesity was compared by the odds ratio (OR) with its 95% confidence intervals (CIs). The statistical significance of the summary OR was determined with the Z-test. Five comparisons were performed between the two groups: frequency of allele (Gln vs. Glu), heterozygote comparison (Gln/Glu vs. Gln/Gln), homozygote comparison (Glu/Glu vs. Gln/Gln), dominant model (Gln/Glu + Glu/Glu vs. Gln/Gln) and recessive model (Glu/Glu vs. Gln/Gln + Gln/Glu) of ADRB2 Gln27Glu. For the rs1042713 (Arg16Gly) polymorphism, we used the same strategy, by replacing Glu27 with Arg16. Five comparisons were performed between two groups: frequency of allele (Arg vs. Gly), heterozygote (Arg/Gly vs. Arg/Arg), homozygote (Gly/Gly vs. Arg/Arg), dominant model (Arg/Gly + Gly/Gly vs. Arg/Arg) and recessive model (Gly/Gly vs. Arg/Arg + Arg/Gly) of ADRB2 Arg16Gly.I2 was also calculated to evaluate the variation caused by the heterogeneity. A high value of I2 indicated a higher probability of the existence of heterogeneity. A random-effects model (DerSimonian and Laird method) was used if substantial heterogeneity was detected . Otherwise, a fixed-effect model was applied in the absence of between-study heterogeneity . The significance of the pooled OR was determined by the Z-test, and the significance was set at P<0.05. Fisher's exact test was used to assess the Hardy-Weinberg equilibrium, and the significance was set at P<0.05. Potential publication bias was estimated using a funnel plot. Egger's linear regression test was used to evaluate the funnel plot asymmetry on the natural logarithmic scale of the OR . We also further investigated the rs1042714 and rs1042713 gene polymorphism with obesity stratifying the population based on gender.In consideration of the possibility of heterogeneity among the studies, a statistical test for heterogeneity was examined by the Chi-square-based Q-test, and the significance was fixed at the level P<0.05. The inconsistency index According to the search strategy, 34 published articles were identified for potential inclusion with full text obtained for ADRB2 polymorphism and obesity. Three articles were excluded because two papers were correspondences Overall, the methodological quality of the 18 studies was modest. In general, the mixture studies including 15 case control studies, one random study, one cross sectional study and one cohort study. The studies failed to protect against selection bias: the definition of obesity used for the study is not uniform. None of the studies used secure methods for ascertainment of exposure. The majority of the studies provided evidence on the reliability of methods for outcome assessment; however, only several studies explicitly stated that outcome assessment was blind to exposure status. Finally, only two publications I2>50%) or a fixed-effect model was applied in the absence of between-study heterogeneity . Meta-analysis of rs1042714 (Gln27Glu) and rs1042713 (Arg16Gly) polymorphism on risk of obesity are shown in I2 = 49%, P = 0.009), indicating that risk of developing obesity with Gln/Glu heterozygotes was 1.16 times higher than those with Gln/Gln homozygotes. Additionally, the dominant model also exhibited a significant difference , suggesting that risk of developing obesity with the Gln/Glu plus Glu/Glu genotype was 1.2 times higher than with the Gln/Gln homozygotes  gene polymorphism, and 10 studies met our criteria for the rs1042713 (Arg16Gly) polymorphism. The frequency of occurrence of ADRB2 Gln27Glu/Arg16Gly allele in the population and their distribution among various populations are presented in ozygotes . On the ozygotes . Our metozygotes .Publication bias was assessed by the funnel plot and Egger's test. The funnel plot (heterozygote Gln/Glu vs. Gln/Gln) showed no apparent evidence of publication bias . There wTaking into account possible gender-specific roles in etiology Several studies involved in ADRB2 polymorphisms and obesity have been published In 2007, Gjesting and colleagues In 2008, Jalba and colleagues Since the association of ADRB2 polymorphisms with obesity is controversial, we conducted this meta-analysis based on all current available data on the relation between ADRB 2 polymorphism and obesity in 18 publications in order to clarify their relationship. Our findings suggest that there is a significant association between rs1042714 polymorphism of ADRB2 and obesity: OR = 0.86 for the allelic genetic model, OR = 1.2 for the dominant genetic model, OR = 0.99 for the recessive genetic model, OR = 1.01 for the homozygote genetic model, OR = 1.16 for the heterozygote genetic model.In dominant comparison, the risk of developing obesity with Gln/Glu plus Glu/Glu genotype was 1.2 times higher than those with Gln/Gln homozygotes. However, our meta-analysis suggested no significant correlation of the rs1042714 (Gln27Glu) polymorphism to obesity in the other three comparisons. Also, no significant correlation to obesity was found for the rs1042713 polymorphism in all genetic models in the total population, as well as in gender-specific populations. This may be due to the divergence in genetic background. For example, the strength of the association between either rs1042713 or rs1042714 and obesity may be variable in different populations. Compared with the study of Jalba et al Though our study provides the most comprehensive and up-to-date meta-analysis regarding the association between ADRB2 polymorphism with obesity, but also evaluates the methodological quality of 18 studies including our meta-analysis. Our work has some limitations. First, obesity is a complicated status involving complex interactions of genes, environment, and other factors, such as diet, lifestyle, diabetes mellitus, hypertension, total cholesterol, triglycerides, HDL and LDL. Though majority of publications included in our meta-analysis considered the factors described above such as diabetic factor, several articles did not consider the factors. See Second, different BMI values were used as a cut-off in enrolling studies. Asian populations require a lower BMI to indicate that an individual is at the same risk as a European, and this variation can be explained by WHO expert consultations Third, our results were based on an unadjusted estimate, a more precise analysis should be performed adjusted by age, smoking, and other factors. Lack of the original data of the enrolled publications limit our further evaluation of potential interactions such as gene-gene, gene-environmental factors, which may affect obesity risk.Lastly, although our funnel plot and Egger's test results showed no evidence of sample selection bias, it is still a remote possibility that such selection bias may have inadvertently occurred, and future meta-analysis studies may wish to recheck these conclusions as new research data continues to be published.In summary, our results clarify that the overall conclusion of the literature to date indicates a significant association of Gln27Glu polymorphism with increased risk of obesity. Interestingly, increased risk of obesity is associated only with the Gln27Glu polymorphism of ADRB2, not the Arg16Gly polymorphism. This result sets the stage for future biochemical studies to investigate the mechanisms underlying this polymorphism-specific risk factor. Our conclusion also provides a basis to recognize patients at higher risk for obesity, allowing clinicians to more accurately create strategies for individualized therapy in obese patients.Table S1Interest declaration of 18 studies included in the meta-analysis.(DOC)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.