CIMT was assessed by high-resolution B-mode ultrasound  images of the common carotid artery using both manual and semiautomated methods . Intraclass correlation coefficient (ICC) and the mean differences of paired measurements (Bland-Altman method) were used to compare both methodologies. The ICC of manual (0.547 ± 0.095 mm) and automated (0.524 ± 0.068 mm) methods was R = 0.74 and an absolute mean bias ± SD of 0.023 ± 0.052 mm was observed. Interobserver and intraobserver ICC were greater for automated (R = 0.94 and 0.99) compared to manual (R = 0.72 and 0.88) methods. Although not considered to be clinically significant, manual measurements yielded higher values compared to automated measurements. Automated measurements were more reproducible and showed lower interobserver variation compared to manual measurements. These results offer important considerations for large epidemiological studies.Carotid intima-media thickening (CIMT) is a marker of both arteriosclerotic and atherosclerotic risks. Technological advances have semiautomated CIMT image acquisition and quantification. Studies comparing manual and automated methods have yielded conflicting results possibly due to plaque inclusion in measurements. Low atherosclerotic risk subjects ( Vascular risk assessment has become integral to good clinical practice. Conventional risk factors which are derived from a patient's family and smoking history, blood pressure, and measurement of blood glucose and lipid levels have been used successfully to derive a person's future risk of developing atherosclerotic cardiovascular disease , 2. MeasOne hundred and twenty-six  subjects were recruited from the general population. The study was approved by Trinity College Dublin Ethics Committee. Written informed consent was obtained from all subjects prior to testing protocols. Subjects were included if they were lifelong never-smokers, free from cardiovascular disease, and normotensive (<140/90 mmHg), had normal lipid profile (LDLc < 4.0 mmol/L), normal fasting glucose (fasting glucose < 6.2 mmol/L), and moderate alcohol intake . Subjects were excluded if they were receiving treatment for or had a history of hypertension, hyperlipidaemia, and diabetes or were taking any medications that affected haemodynamic and/or metabolic responses.Subjects attended the Cardiovascular Research Unit at Tallaght Hospital. Various anthropometrical measurements were recorded, including height , weight , and waist/hip circumference .High-resolution B-mode ultrasound images of the right and left common carotid artery were used to measure carotid intima-media thickness. Patients were scanned in the supine position using 7–12 MHz linear array transducer .CIMT was calculated using both manual  and semiautomated  methods. Manual CIMT measurements were recorded from the far wall at 1 cm, 1.5 cm, and 2 cm intervals proximal to the carotid bulb . AutomatPearson product-moment correlation coefficient and the intraclass correlation coefficient (ICC) were used to examine the relationship between manual and automated methods . The assThe technical error of measurement (TEM) and ICC of ten randomly selected subjects were used to identify intraobserver reproducibility and interobserver reliability of the two methods , 16.t-test was used to compare gender differences . Values are reported as mean ± SD unless otherwise stated.An unpaired P < 0.049).Subject characteristics and cardiovascular risk factors are outlined in r = 0.80; P < 0.0001) between manual  and automated  methods; however, the same association was not observed with ICC (R = 0.74).Pearson correlation demonstrated strong association  identified an absolute mean bias and SD of −0.023 ± 0.052 mm between manual and automated CIMT measurements with limits of agreement of 0.078 to −0.125 mm .R = 0.94 and 0.99) compared to manual (R = 0.72 and  0.88) methods.The TEM, quantifying the interobserver reproducibility and intraobserver variability, was lower for automated (3.71% and 1.52%) compared to manual (8.11% and 6.30%) methods. As a consequence, the interobserver and intraobserver ICC was greater for automated  [In the present study, Pearson product-moment correlation coefficient demonstrated a strong association between both methods; however, a strong ICC was not observed ( < 0.85) . Pearson < 0.85) . This waPrevious studies report no differences between automated versus manual CIMT methodologies whereas other studies report significantly greater values using manual techniques , 10, 12.Seçil et al.  reportedr = 0.86; P < 0.01) between automated and manual methodologies with no observable systematic bias in the mean differences (mean difference 0.023 ± 0.034 mm). The authors also reported lower interobserver and intraobserver variation coefficients for automated methods (6.6% and 5.6%) compared to manual methods (14.1% and 11.1%). More recently, Yanase et al. [Freire et al.  reportedFor the present study, in order to minimise potential measurement inconsistencies caused by abnormal CIMT, focal thickening, or the presence of atheromatous lesions, only subjects with very low cardiovascular risk were recruited. In addition, manual CIMT measurements were averaged from three anatomic sites, over several cardiac cycles from both left and right sides. Despite these precautions, it is possible that outliers may have caused an overestimation of manual CIMT . For autThis study does not examine serial changes in CIMT over given time intervals. Such measurements are used in clinical practice as surrogate markers of vascular risk . Larger Most large scale epidemiological studies have adopted manual methodologies to quantify CIMT with only one study using semiautomated edge detection software , 21–23. In conclusion, semiautomated measurements of CIMT yield significantly lower values compared to manual measurements and produce lower intraobserver and interobserver variation. Although the differences between manual and automated methods are small and may not be clinically significant, these observations offer important considerations for large epidemiological or longitudinal studies.


The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis.The previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping.P = 0.006, OR = 0.83, 95% CI = 0.72–0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69–1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53–1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model  and AC vs. AA .Neither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: The MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study. Cervical cancer is the third most frequently encountered cancer and the fourth leading cause of the women’s cancer death in the world, accounting for 9%  of the total newly-diagnosed cancer cases and 8%  of the total cancer deaths among females in 2008 Association between micronutrient depletion, particularly folate deficiency, and cervical lesions has been studied for a long time. Folate deficiency, as a potential risk for cervical cancer, was first reported by some cytopathologists in the 1960s, who had found that the cervical epithelial cells from folate-deficient women had some similarity to the dysplastic cervical cells in cytology The apparent role of folate in carcinogenesis in cervical tissue has stimulated investigations of polymorphisms in the folate metabolizing enzymes. As we know, Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme that can regulate the metabolism of folate and methionine, both of which are important in DNA methylation and synthesis Several studies had been designed to evaluate associations between MTHFR genotypes and cervical lesions, including cervical cancer, but the results were inconsistent because of different stages of cervical lesions and the combinatorial effects of other risk factors. Precancerous cervical lesions are classified according to the degree of cellular abnormality. The lowest grade of abnormality is CIN1, and CIN2 and CIN3 describe the progressive epithelial dysplasia leading to invasive cancer. Preinvasive lesions have also been classified in terms of squamous intraepithelial lesions (SILs) included low-grade squamous intraepithelial lesions  and high-grade squamous intraepithelial lesions . The majority of the case-control genetic studies revealed no association between cervical lesions and MTHFR SNPs These inconclusive results may due to limited sample size, because any single study may be underpowered to detect the precise effects. In addition, there also may be the causes of different characteristics among studies, such as ethnicity, pathological history, sources of controls, and source of DNA for genotyping. Therefore, we have done a meta-analysis on association between MTHFR polymorphisms and cervical lesions using data obtained from the published case-control genetic studies. Our aim was to identify whether the MTHFR polymorphisms affect the susceptibility to SIL or cervical cancer by means of a large-scale meta-analysis. Furthermore, we wanted to summarize the effect size of the polymorphism associated with the susceptibility to the cervical lesions.The computer-based search strategy was comprehensively used to find eligible studies for this meta-analysis. Two investigators  searched in the PubMed and Emase independently from inception to July 22, 2012, for the studies on the association between the MTHFR C677T polymorphism (rs1801133) and A1289C polymorphism (rs1801131) and the cervical lesions. Following Medical Subject Heading (MeSH) terms and/or text words were used in our search, such as for methylenetetrahydrofolate reductase (“MTHFR” or “methylenetetrahydrofolate reductase” or Methylenetetrahydrofolate Reductase AND (NADPH2)) with terms for genetic variations  and terms for cervical lesions. Meanwhile, China Biological Medicine Database (CBM) was also searched for the eligible studies. Full articles published in English or Chinese were considered to be eligible for our study. In addition, reference list of the original research articles and reviews were also manually searched.The eligible studies must meet the following inclusion criteria: (1) Exploration of associations between the MTHFR genetic polymorphisms (including C677T or A1298C or both) and the susceptibility to cervical cancer or SIL; (2) A case-control study; (3) Provision of information on genotype frequencies of the MTHFR C677T and/or A1298C polymorphism(s) or sufficient data for the calculation. The exclusion criteria were as follows: (1) A review, case report, editorial, or comment; (2) A duplicated study; (3) Laboratory molecular or animal studies. If studies contained overlapping cases and/or controls, the largest study with extractable data was preferred.Because the data included in this study was taken from literatures, written consent given by the patients and ethical approval acquired by certain committee were not needed in our meta-analysis.According to the inclusion and exclusion criteria, extraction from each study was conducted independently by two authors  and the consensus was achieved for all the data, which were as follows: the first author’s name, year of publication, source of controls, source of DNA for genotyping, country, ethnicity, goodness-in-fitness of Hardy-Weinberg Equilibrium (HWE) in the control group, histological stage of cervical lesions, numbers of cases/patients and controls, and distribution of genotypes in the case and control groups. The patients were recruited into the study regardless of whether they had a first-degree relative with cervical lesions. The controls were recruited regardless of whether they had other diseases, e.g., hysteromyoma. For studies with inadequate information, authors of those studies were contacted for further information by E-mail if possible.vs. AA), recessive model (aa vs. Aa+AA) and additive model (A vs. a). Moreover, the pooled estimates were also calculated for the pair-wise comparisons . The above-mentioned A and a represented the major and the minor allele respectively. Taking consideration of possible between-study heterogeneity, a statistical test for heterogeneity was performed by the χ2 test or Fisher exact test when appropriate. P<0.10 or I2>50% indicated an obvious of the between-study heterogeneity, and OR (95% CI) was calculated by the random-effects model using the DerSimonian and Laird method; otherwise, the fixed-effects model was used by the Mantel-Haenszel method Meta-analysis was performed and reported as described previously P<0.05 was considered a statistical significance The allele frequencies, at which the MTHFR C677T/A1298C polymorphisms occurred in each respective study, were determined by the allele-counting method. A chi-square test was used to determine whether the observed frequencies of the genotypes in the controls conformed to Hardy Weinberg-Equilibrium (HWE) expectations if genotype data were available. Sensitivity analyses were performed on stability of the results, namely, one case-control study omitted each time to reﬂect the inﬂuence of the individual data set on the pooled OR. Several methods were used to detect any probable publication bias. Asymmetry of the funnel plot indicated the possible publication bias. In addition, the Egger and Begg quantitative tests were also used, and P values were two-sided. To ensure the reliability of data, two reviewers  independently performed the data analysis using the statistics programs for the same results.All analyses were performed using the RevMan 5.0 program  and the STATA package version 11.0 program . All P>0.05). However, two of the studies vs. CC or AC/CC vs. AA) were available. Therefore, this study was included in the analysis on the dominant model, not on other genetic models. Furthermore, the allele and genotype frequencies, at which the MTHFR C677T and the A1298C polymorphisms occurred in case and controls in each of the studies, were also summarized  and the random-effects model was used in the meta-analysis. The subgroup analysis of the C677T polymorphisms in the histological stages of the cervical lesions also revealed that the polymorphism was not associated with the risk of ICC or SIL in all the genetic models . The heterogeneity was significantly reduced in the Europe populations in the recessive, additive, C/T vs. C/C, and T/T vs. C/C models.As for the C677T polymorphism, no association was found between the polymorphism and the susceptibility to cervical lesions in all the genetic models  and the random-effects model was performed. However, there was no significant heterogeneity for the comparison of other genetic models (P>0.1) and the fixed-effects method was performed for our investigation. In the subgroup analysis, no association was found between the A1298C polymorphism and SIL. Interestingly, the investigation on the women with A1298C polymorphisms vs. no carriers showed a marginally increased susceptibility to ICC but no statistically significant difference in dominant model  and AC vs. AA .As for the A1298C polymorphism, no association was found between the polymorphism and the cervical lesions in all the genetic models , none of them could sufficiently explain the heterogeneity. The effect estimates might depend on some unidentified sources of heterogeneity. Besides, part of the exposure information was still lacking in the available studies, E.g., HPV infection status, smoking status or nutritional status (particularly folate intake or level). Therefore, effects of environment exposure or lifestyle on association between MTHFR variants and cervical lesions could not be determined by this meta-analysis.In summary, despite the above-mentioned limitations, the present study provides evidence that the MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical cancer development. However, our meta-analysis reveals a negative association between the MTHFR C677T mutations and cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility for cervical cancer need to be further studied.Table S1PRISMA checklist.(DOC)Click here for additional data file.


GCK rs1799884, GCKR rs780094, MTNR1B rs10830963 and G6PC2 rs560887, which are related to fasting plasma glucose levels, increase the risk of type 2 diabetes mellitus (T2DM) is contradictory. We therefore performed a meta-analysis to derive a more precise estimation of the association between these polymorphisms and T2DM.The evidence that the variants All the publications examining the associations of these variants with risk of T2DM were retrieved from the MEDLINE and EMBASE databases. Using the data from the retrieved articles, we computed summary estimates of the associations of the four variants with T2DM risk. We also examined the studies for heterogeneity, as well as for bias of the publications.GCK (rs1799884), GCKR (rs780094) and MTNR1B (rs10830963) were significantly associated with T2DM susceptibility . After stratification by ethnicity, significant associations for the GCK, MTNR1B and G6PC2 variants were detected only in Caucasians , but not in Asians .A total of 113,025 T2DM patients and 199,997 controls from 38 articles were included in the meta-analysis. Overall, the pooled results indicated that GCKR rs780094 variant confers high cross-ethnicity risk for the development of T2DM, while significant associations between GCK, MTNR1B and G6PC2 variants and T2DM risk are limited to Caucasians.Our meta-analyses demonstrated that  GCK, rs1799884), glucokinase regulator protein , islet specific glucose-6-phosphatase  and melatonin receptor 1B  to be the variants that most influence FPG levels Previous epidemiological studies have provided compelling evidence that fasting plasma glucose (FPG) levels that are on the high side of the normoglycemic range are associated with increased risk of type 2 diabetes mellitus (T2DM) GCK encodes the key enzyme for the first step of glycolysis and is expressed only in liver and pancreatic islet beta cells GCKRG6PC2 is also known as the encoding gene for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), which is expressed in a highly pancreatic beta-cell-specific manner. But its catalytic activity has not been clearly described so far MTNR1B encodes a melatonin receptor that is found mainly in the brain. However, the presence of this receptor in islets suggests a possible association between its function and insulin secretion et al. found the GCK rs1799884 polymorphism was associated with impaired glucose regulation et al. reported that the G-allele of GCKR rs780094 polymorphism was associated with a modest increased risk of T2DM et al. provided evidence that the risk genotype of the MTNR1B rs10830963 variant could predict future T2DM et al. reported a significant association between the G6PC2 rs560887 variant and T2DM risk et al. demonstrated that there were combined effects of these four single nucleotide polymorphisms (SNPs) on FPG levels and T2DM risk et al. failed to validate the association between genetic variants in GCK, GCKR, MTNR1B, G6PC2 and T2DM in a Chinese population et al. in a south Asian population Because of the significant impact of these variants on FPG, numerous studies have investigated further the association between these variants and T2DM risk. Rose GCK, GCKR, MTNR1B and G6PC2) and disease name  to retrieve the association studies between genetic variants in GCK, GCKR, MTNR1B and G6PC2 and risk of T2DM. The computer-aided search was supplemented by including additional studies retrieved from the references and citations of the originally identified articles and from the PubMed option ‘Related Articles’.We conducted a systematic literature search (up to December 2012) of the MEDLINE and EMBASE databases in accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement GCK, rs780094 in GCKR, rs10830963 in MTNR1B and rs560887 in G6PC2) were finally included. Studies that met all the following criteria were included: (1) published in English; (2) with primary outcomes of T2DM; (3) described ethnicity and numbers of the study population; (4) provided the odds ratio (OR) with 95% confidence intervals (CIs) or enough genotype distribution data to calculate the ORs and 95% CIs. The exclusion criteria included: (1) not an association study for T2DM; (2) case-only study; (3) studied other SNPs; (4) meta-analysis. For duplicate publications, the study with the smaller data set was excluded.Although several SNPs in the four studied genes have previously been linked to FPG levels and T2DM, only those variants that were studied in a total of >50,000 cases were analyzed. As a result, four SNPs  extracted data independently and in duplicate. All disagreements and uncertainties were discussed and resolved by consensus, with the involvement of another author (H.D.) if necessary.The same two authors assessed the quality of included studies independently according to a quality assessment scores which was developed based on traditional epidemiologic and genetic considerations 2I test. 2I test values of 25%, 50% and 75% were considered low, moderate and high, respectively p<0.05), the source of heterogeneity was explored by fitting a co-variant  in a meta-regression model. Furthermore, considering the possible impact of ethnic variations on the results, we divided the study populations into three ethnic subgroups, including Caucasians, Asians and others. And differences between the subgroups were compared using the χ2 based Q test p<0.05 were considered to be statistically significant and values of p<10−8 were considered to have reached a genome-wide significance level. All analyses were performed using the STATA software version 10.0 .Data analyses were performed as follows. Firstly, we calculated the pooled prevalence of each risk allele in various ethnic groups using the inverse variance method described previously A total of 509 articles from MEDLINE and EMBASE were identified through the preliminary literature search up to December 2012. As shown in 2 = 1.0) and rs730497 (r2 = 1.0) across different racial populations , respectively. Therefore, the SNP rs1799884, which tags rs4607517 and rs730497, is probably the best proxy to evaluate the effect of this gene. Totally, 20 articles involving 91,328 cases and 169,119 controls were included to evaluate the effect of rs1799884 (or as proxy) for T2DM risk. As shown in GCK rs1799884 was significantly associated with increased risk of diabetes , with moderate heterogeneity .Not all researchers used the same SNPs. The most widely used was rs1799884. The remaining 5 articles used 2 additional SNPs, rs4607517 and rs730497. Based on 1000 genome project, the SNP rs1799884 was in strong linkage disequilibrium (LD) with rs4607517 . The results indicated that the minor A-allele might be associated with an augmented T2DM risk  in Caucasians. However, no clear evidence for such an association was observed in either Asians  or others .After being stratified for ethnicity, significant difference between ethnic groups was detected (subgroup difference χp = 3.8×10−6) with high heterogeneity among studies . After being stratified for ethnicity, significant associations were observed both in Caucasians  and Asians , with no difference in ORs observed .In total, 20 studies from 17 independent publications investigating the influence of the rs780094 on the risk of T2DM were combined, yielding a meta-analysis of data from 236,778 individuals . As presented in p = 0.002).Meta-analysis on the relationship between rs10830963 and T2DM risk included 18 independent articles containing data from 227,436 subjects . As shown in 2 = 52.2%; p = 0.002), and an inconsistent effect was noted when studies were considered separately by ancestry . Indeed, the association between the minor G-allele and T2DM risk was well replicated and reached a genome wide significance level in populations of Caucasians , but it is not replicable in Asians .A high level of heterogeneity was observed between the included studies , with moderate heterogeneity . However, when considered separately by ethnicity, a contrasting effect of this variant on T2DM was observed . Results from Caucasian studies indicated the FPG-raising G-allele might be associated with a decreased risk of T2DM , with no heterogeneity observed . Conversely, in Asians, the G-allele was associated with increased risk of T2DM, although statistically not significant . Given the low frequency and limited sample size of Asian studies, the current meta-analysis may be still be under-powered to provide conclusive insights into this issue.We pooled data from 6 articles containing a total of 55,569 cases and 106,414 controls. As indicated in p>0.05).In the meta-regression analyses, neither sample size, study quality, mean age of cases and controls nor sex distribution in cases and controls were significantly correlated with the magnitude of the genetic effect . Besides, in the sensitivity test , the leave-one-out influential analyses showed that no individual study would significantly modify the estimates, and this further confirmed the stability and reliability of the pooled results.Based on Begger’s funnel plots  and Egger’s linear regression, we didn’t detect any publication bias for all the pooled analyses  and unpublished work would have been missed, and publication bias may potentially exist. Third, because no original individual data were available, we were not able to further investigate the cumulative effect of the included variants and the gene-environment interactions could not be investigated.GCKR rs780094 polymorphism is an important variant that confers high cross-ethnicity risk for development of T2DM. Conversely, significant associations between the GCK, MTNR1B and G6PC2 variants and T2DM risk are limited to Caucasians, and the meta-analysis results of associations of those variants with T2DM are required for further evaluation in larger sample size in Asian population.In conclusion, our meta-analysis has provided robust evidence that the Figure S1Begg’s funnel plot of studies of the GCK rs1799884 variant and T2DM. Each point represents a separate study for the indicated association. Egger’s test, t = −0.42, p = 0.678.(TIF)Click here for additional data file.Figure S2Begg’s funnel plot of studies of the GCKR rs780094 variant and T2DM. Each point represents a separate study for the indicated association. Egger’s test, t = 0.86, p = 0.401.(TIF)Click here for additional data file.Figure S3Begg’s funnel plot of studies of the MTNR1B rs10830963 variant and T2DM. Each point represents a separate study for the indicated association. Egger’s test, t = −1.31, p = 0.205.(TIF)Click here for additional data file.Figure S4Begg’s funnel plot of studies of the G6PC2 rs560887 variant and T2DM. Each point represents a separate study for the indicated association. Egger’s test, t = 1.35, p = 0.225.(TIF)Click here for additional data file.Figure S5Sensitivity analyses of the GCK rs1799884 variant in an additive model by omitting one study at a time. The summary OR (95% CI) was indicated by each horizontal line when the labeled study was omitted and the reminders were reanalyzed.(TIF)Click here for additional data file.Figure S6Sensitivity analyses of the GCKR rs780094 variant in an additive model by omitting one study at a time. The summary OR (95% CI) was indicated by each horizontal line when the labeled study was omitted and the reminders were reanalyzed.(TIF)Click here for additional data file.Figure S7Sensitivity analyses of the MTNR1B rs10830963 variant in an additive model by omitting one study at a time. The summary OR (95% CI) was indicated by each horizontal line when the labeled study was omitted and the reminders were reanalyzed.(TIF)Click here for additional data file.Figure S8Sensitivity analyses of the G6PC2 variant in an additive model by omitting one study at a time. The summary OR (95% CI) was indicated by each horizontal line when the labeled study was omitted and the reminders were reanalyzed.(TIF)Click here for additional data file.Table S1Quality score assessment criteria.(DOCX)Click here for additional data file.Table S2Estimation of the pooled prevalence of the risk A-allele of GCK rs1799884.(DOCX)Click here for additional data file.Table S3Estimation of the pooled prevalence of the risk C-allele of GCKR rs780094.(DOCX)Click here for additional data file.Table S4Estimation of the pooled prevalence of the risk G-allele of MTNR1B rs10830963.(DOCX)Click here for additional data file.Table S5Estimation of the pooled prevalence of the risk A-allele of G6PC2 rs560887.(DOCX)Click here for additional data file.Table S6PRISMA Checklist for the current meta-analysis.(DOC)Click here for additional data file.Table S7PRISMA Flow Diagram for the current meta-analysis.(DOC)Click here for additional data file.


The Roma (Gypsies) are a transnational minority, founder population characterized by unique genetic background modeled by culturally determined endogamy. The present study explores whether the widely found cardiovascular diseases (CVD) risk effects of ACE I/D, APOE , eNOS-VNTR and LEP G2548A polymorphisms can be replicated in this specific population.The community-based study was carried on 208 adult Bayash Roma living in rural settlements of eastern and northern Croatia. Risk effect of four CVD candidate polymorphisms are related to the most prominent classical CVD risk phenotypes: obesity indicators (body mass index and waist circumference), hypertension and hyperlipidemia . For all of them the standard risk cut-offs were applied. The extent to which the phenotypic status is related to genotype was assessed by logistic regression analysis. The strongest associations were found for ε2 allele of the APOE as a predictor of waist circumference  as well as for BMI . It is notable that ε3 allele of APOE gene turned out to be a protective genetic factor determining low lipid levels.The strength of the relation and the similarity of the results obtained for both tested indicators of obesity provide firm evidence that APOE plays an important role in obesity development in the Roma population. The Roma are a transnational minority population of Indian origin fragmented in numerous, often endogamous, smaller groups dispersed throughout Europe, in which the influence of genetic drift is highly emphasized -3. The RA total of 230 adult members of the Roma population (78 men and 152 women) aged 20-84 yrs (50.1 ± 14.1) living in rural settlements in Eastern and Northern Croatia were included in the study. All examinees voluntarily participated and before signing the informed consent were informed about the goals, methods and expectations of the study. The study protocol was approved by the local Ethical Committee.Small samples of peripheral blood (7.5 ml) were collected for genetic and core biochemical analyses . DNA was extracted from blood samples using the salting out method. Alu I,D (ACE), G-2548A (LEP), VNTR-4,5 (eNOS), and ε2, ε3, ε4 (APOE) polymorphisms were genotyped by applying respective methods .2) and waist circumference [Short anthropometry was undertaken  and the mference . Blood pAllele frequencies were calculated from genotype frequencies. Deviation from Hardy-Weinberg equilibrium was assessed by exact test. All data  were analyzed univariately using standard statistical methods for quantitative and qualitative variables (data not shown). For each CVD risk phenotype the genotypic odds ratios of selected polymorphisms were estimated using logistic regression analysis including combined effects of sex, age, and other biological covariates. For all studied polymorphisms each homozygote genotype was tested against the other two genotypes. All analyses were performed by SPSS 10.0 statistical package.The prevalence of CVD risk phenotypes in this sample together with employed standard cut-off values  is presented on Table Genotype and allele frequencies (N & %) for all four examined CVD candidate polymorphisms ) in Croatian Roma are presented in Table The relations of all CVD phenotypes with four candidate polymorphisms were tested by logistic regression analysis. The independent variables were tested as quantitative and qualitative ones and the better variant for each phenotype was used. The best models of logistic regression analyses are presented in Table The most significant relation among the investigated CVD risk phenotypes and the four candidate polymorphisms was found between APOE ε2 and obesity indicators (variables: Waist_C and BMI25). The best logistic model explains 34.4% of Waist_C variance and shows that ε2 allele (i.e. genotypes ε2ε3 and ε2ε4) increases the risk of high Waist_C phenotype by 3.301 times . Similarly significant findings have been obtained for the variable BMI25 where the best model shows that ε2 allele increases the risk of having BMI >25 by 3.547 times .Neither allele, genotype nor their combination presented itself as a risk for hypertension, elevated triglycerides, total, LDL or HDL cholesterol. However, two significant findings emerged and they were related to decreased risk of hyperlipidemia. This protective relation showed the combination of allele ε3 (APOE) and genotype 55 (eNOS) for the triglyceride level and the same combination with addition of genotype II (ACE) for LDL. 141 participants (71.6%) of the study had the former protective combination and 31 participants (15.8%) had the later combination.Numerous studies revealed the influence of APOE genotypes on lipid and lipoprotein levels. Generally it was shown that ε2 allele is associated with decreased and ε4 with increased total cholesterol level -18. The Some studies showed that ε2 allele carriers have decreased apoE receptor binding capacity in liver, and transport of VLDL and chylomicrons from blood to hepatocytes, than ε3 and ε4 carriers ,19. The Therefore, it is possible that gene-nutrition interactions ,23 are rThe study's weakness is its limited sample size and it must therefore be regarded as preliminary to larger investigations. These will include the analysis of family data directed towards confirming linkage between APOE ε2, ε3, ε4 polymorphism and obesity phenotype. Additionally, the apolipoprotein E gene-nutrition interactions are planned to be examined in more detail.The main strength of the study is that it was performed without presumptive hypothesis about the effect of particular genotypes and thus the possible impact of each genotype was explored alone and in combination with other genetic and environmental factors. This approach enabled the effect of E2 allele to emerge.In conclusion, APOE polymorphism is a major determinant of CVD risk in the Croatian Roma acting on several phenotypic risk traits - obesity indicators and lipid levels (LDL and triglycerides). While the protective role of ε3 allele and the risk of ε2 and ε4 is not a novel finding, the strength of the relation of ε2 allele with obesity indicators is a remarkable result of the present study.The authors declare that they have no competing interests.HMZ participated in the design of the study and drafted the manuscript. TŠJ, BS and NSN participated in the design of the study, contributed to acquisition of data and its interpretation, performed the statistical analysis and helped to draft the manuscript. ŽT, AB, and MPS carried out the molecular genetic study, participated in the sequence alignment and contributed to acquisition of data and its interpretation. BJ conceived the study, participated in its design and coordination and contributed to acquisition of data and its interpretation. All authors read and approved the final version of the manuscript.


IARC Monographs staff have occasionally conducted meta-analyses prior to a monograph , formal meta-analyses are not prepared routinely for the evaluations. However, such meta-analyses can be considered when they are publicly available and, as stated in the “Preamble to the IARC Monographs,” “ad-hoc calculations that combine data from different studies may be conducted by the Working Group during the course of a Monograph meeting” (IARC 2012).The IARC Monograph Working Group met in 2009 , but theIARC Monograph procedures were first developed. As Although meta-analyses have been widely used in social sciences and medical research for decades, it is only recently that they have become more widely used in epidemiology , and theEpidemiologic studies of specific topics have tended to be fewer [than is the case in social science or medicine], and the epidemiologic community appears to be more hospitable to tentative, limited inferences based on narrative reviews. Nonetheless, to neglect quantitative aspects of review would be akin to presenting a study and supplying only a narrative discussion of the raw data, with no attempt to group and compare subject outcomes.Having participated in several Monograph Working Groups, we know that informal meta-analyses are performed by members of the working groups (at least by ourselves) because this is one of the standard ways to quantitatively summarize the evidence. Meta-analyses can be challenging and controversial depending on assumptions, particularly for studies on occupational and environmental exposures that frequently are not easy to quantify. Certainly meta-analyses cannot be done for all agents evaluated by IARC, and results of meta-analyses have to be critically interpreted in a manner similar to that of all other data.Monographs evaluations, incorporating the systematic inclusion of biological knowledge into the criteria for the classifications, and has also updated the whole process for other items, such as conflict of interest and the prodecure for the selection of participants. These changes have strengthened the validity and acceptance of these evaluations. Given the international importance of the IARC Monographs, it seems advisable to use all the tools available for summarizing the scientific evidence, one of which is meta-analysis. The meta-analysis by Even without using formal procedures for a quantitative summary of the epidemiological evidence, IARC Working Groups reach conclusions that are seldom seriously challenged, particularly for Group 1 carcinogens. This is probably because IARC Working Groups tend to express the consensus in the scientific world. When they occasionally have made controversial decisions, for example the 1997 dioxin evaluation reclassifying TCDD from a Group 2B (possible) carcinogen to Group 1, they seem to have been proven right by later research. IARC has revised procedures for the


However, the results were conflicting and controversial.Several studies evaluated the associations of Databases including PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Data were extracted independently by two investigators. Crude odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated.TNF-α −308A/G polymorphism and pneumonia risk was observed for AA +AG vs. GG . In addition, TNF-α −308A/G polymorphism was not associated with pneumonia mortality . Furthermore, there was no association of TNF-α −238A/G polymorphism with the risk of pneumonia .Twelve case-control studies and one cohort study were included. Overall, no association between TNF-α −308A/G, −238A/G polymorphisms were not associated with pneumonia risk. Moreover, TNF-α −308A/G polymorphism did not play a role in the pneumonia mortality risk. Excessive TNF-α production contributed to lung injury in a variety of diseases TNF-α gene is located on chromosome 6, within the class III region of MHC. Several polymorphisms in the promoter region of TNF-α, such as −238A/G (rs361525), −308A/G (rs1800629), −857G/A (rs1799724), and −1031T/C (rs1799964), have been identified. These polymorphisms could alter the expression of TNF-α TNF-α polymorphisms and the risk and outcomes of pneumonia TNF-α polymorphisms were associated with an increased risk of pneumonia or higher pneumonia mortality. To our knowledge, this was the first meta-analysis of the associations between TNF-α polymorphisms and pneumonia risk and mortality.The electronic databases of PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched. The following search terms were used:  and (tumor necrosis factor or TNF or tumor necrosis factor-α or TNF-α) and (polymorphism or mutation or variant). Last search was updated in January 23, 2013. Additional relevant references cited in searched articles were also retrieved. No language restrictions were applied.TNF-α polymorphisms and risk of pneumonia or pneumonia mortality, (2) using a case-control design or cohort design, (3) sufficient data for estimating an odds ratio (OR) and 95% confidence interval (CI). Studies were excluded if one of the following criteria existed: (1) not relevant to TNF-α polymorphisms, TNF-α, pneumonia, or pneumonia mortality, (2) non-clinical studies, (3) reviews or abstracts, and (4) not reported genotype frequencies or numbers. For the overlapping studies, only the one with the largest sample size was included in our study.The included studies should meet the following criteria: (1) evaluation of the Two investigators (Li and Nie) assessed the quality of each study independently. Any disagreement was resolved by consensus. The predetermined quality assessment criteria were modified from a previous review TNF-α polymorphisms, and genotype numbers in cases and controls. Two independent reviewers (Li and Nie) collected these data and any discrepancy was resolved by discussion. Authors of the included studies were contacted via E-mail if further study details were needed.The following data were collected from each study: the first author's surname, publication year, ethnicity, age group, type of pneumonia, severity of disease, outcome , sample size, genotyping method, TNF-α −308A/G, −238A/G polymorphisms and the risk of pneumonia and mortality. For this meta-analysis, we examined the dominant genetic model (AA+AG vs. GG) because data were most commonly either presented in this format or convertible to this format. Crude ORs with 95% CIs were computed to assess the strength of the associations. The statistical significance of OR was determined with Z test.Where the data from at least three similar studies were available, meta-analysis was performed. Thus, we evaluated the strength of associations between I2 statistic were used to assess the degree of heterogeneity among the studies included in the meta-analysis. A P value greater than 0.10 for the Q-test indicated a lack of heterogeneity among studies, so that the pooled OR estimate of each study was calculated by the fixed-effects model. Otherwise, the random-effects model was used. Subgroup analyses were carried out by ethnicity, type of pneumonia, and severity of disease. Sensitivity analysis was performed by excluding the low quality studies and excluding the study not in HWE. Publication bias was evaluated with the funnel plot and the linear regression asymmetry test by Egger et al. P value<0.05 was considered statistically significant. Bonferroni correction of critical P values was applied when performing a high number of comparisons. In order to avoid spurious positives, the alpha value was lowered to account for the number of comparisons being performed.Departure from Hardy-Weinberg equilibrium (HWE) in controls was tested by the Chi-square test. The Q statistic and the Our search strategy yielded 306 articles for review. TNF-α −308A/G polymorphism and pneumonia risk P = 0.07) (P = 0.0008) but not among Caucasians . Subgroup analysis was also performed by the type of pneumonia. No increased risk was found among CAP patients . In the subgroup analysis by the severity of pneumonia, significant increase of severe pneumonia risk was found among the A allele carriers . No significant association was found between TNF-α −308A/G polymorphism and non-severe pneumonia risk .Eleven studies determined the association between  = 0.07) Figure 2TNF-α −308A/G polymorphism and pneumonia mortality risk TNF-α −308A/G polymorphism and mortality with an OR of 1.96 . In the subgroup analysis by ethnicity, no association was found among Asians . Stratification by pneumonia type showed that CAP patients carrying A allele were not associated with mortality risk . Furthermore, there was no significant association between TNF-α −308A/G polymorphism and severe pneumonia mortality risk . Summary results of comparisons are listed in Seven studies identified the association between TNF-α −238A/G polymorphism and pneumonia risk P = 0.20) (Seven studies (2235 cases and 2673 controls) studied the association between  = 0.20) Figure 4In order to assess the stability of the results of the meta-analysis, sensitivity analyses were performed by omitting the low quality studies TNF-α −308A/G polymorphism and pneumonia risk, no significant between-study heterogeneity was observed in the dominant genetic model (Pheterogeneity = 0.13 and 2I = 33%). For TNF-α −308A/G polymorphism and mortality risk, there was statistically significant between-study heterogeneity in the dominant genetic model (Pheterogeneity = 0.01 and 2I = 64%). In the CAP subgroup, no significant heterogeneity was found (Pheterogeneity = 0.19 and 2I = 34%). For TNF-α −238A/G polymorphism and pneumonia risk, there was also statistically significant between-study heterogeneity (Pheterogeneity = 0.0009 and 2I = 74%). As shown in Pheterogeneity = 0.30 and 2I = 16%).For P = 0.191).Publication bias was examined by funnel plot qualitatively and estimated by Egger's test quantitatively. The shape of the funnel plot seemed almost symmetrical Figure 5TNF-α −308A/G, −238A/G polymorphisms and risk and mortality of pneumonia. We found that −308A/G polymorphism was not a risk factor for developing pneumonia in the overall study population. In the subgroup analysis, however, we noted that individuals carrying A allele had increased pneumonia risk in Asians, but not in Caucasians. This result indicated that interactions between different ethnicities and genetic variants may contribute to pneumonia risk. We also carried out subgroup analysis for type of pneumonia. No evidence supported the association between this polymorphism and risk of CAP. However, we found that patients with A allele had increased severe pneumonia risk, suggesting a possible role of −308A/G polymorphism in severe pneumonia pathogenesis. Although subgroup analyses found significant associations among Asians and patients with severe pneumonia, we should exercise great caution in interpreting apparent results. Chance is the explanation for spurious subgroup analyses. Thus, these results should be validated by future studies.This meta-analysis of 13 studies systematically evaluated the associations between A non-significant result was observed for the association of −308A/G polymorphism with pneumonia-related mortality. Teuffel and colleagues also did not find an association between this polymorphism and mortality from sepsis in their meta-analysis TNF-α −238A/G polymorphism may play a possible role in the pneumonia-related mortality. However, there were only two studies estimated this association and meta-analysis could not be conducted. This issue is needed to be further studied.Results from our meta-analysis showed the lack of association between −238A/G polymorphism and pneumonia risk. Subgroup analyses also did not detect significant association between this polymorphism and pneumonia risk. These results suggested that −238A/G polymorphism might have no role in the etiology of pneumonia. However, the study from Pappachan et al. Escherichia coli growth both in vitro and in vivo. In addition, systemic administration of TNF-α in rat worsened pneumonia by reducing alveolar neutrophil recruitment and bacterial clearance TNF-α gene could influence the expression of TNF-α Pneumonia is a complex inflammatory disease. Moderate degree of local inflammation is required to control infection; however, excessive release of inflammatory cytokines favours intracellular and extracellular bacterial growth and organ dysfunction TNF-α −238A showed a significantly decreased transcriptional activity. Furthermore, Huizinga and coworkers revealed that the multiple sclerosis patients with −238 GA produced lower TNF-α compared to those with −238 GG Kaluza et al. We should address the importance of heterogeneity and publication bias, which might influence the results of meta-analysis. In our meta-analysis, significant heterogeneity was observed in −308A/G and mortality risk and also in −238A/G and pneumonia risk. Subgroup analysis was used to explore the sources of heterogeneity. After subgroup analysis by the the type of pneumonia, the heterogeneity was effectively decreased in the CAP subgroup. Therefore, it could be speculated that the large heterogeneity mainly resulted from the type of pneumonia. In addition, funnel plot and Egger's test were performed to find potential publication bias. No significant publication bias was noted. Furthermore, we carried out the sensitivity analysis. Removal of the low quality studies or the HWE-violating study did not change the conclusions of meta-analysis. These procedures suggested that our results were stable and robust.Several limitations of this meta-analysis should be considered when interpreting results. First, the number of included studies was moderate. It was possible that some relevant published studies or unpublished studies with negative results were missed. Second, most of the studies were conducted in Caucasian and Asian populations. Therefore, our results may be applicable only to these ethnic groups. Third, because insufficient data could be extracted from the primary publications, we could not assess the effects of +488A/G, −1031T/C, −863C/A, −857C/T, and −376G/A polymorphisms on pneumonia risk and mortality risk. Fourth, the overall outcome was based on unadjusted data, whereas a more precise analysis could be performed if individual data were available to allow adjustment. Finally, pneumonia is a complex disease, and many genes are related to pneumonia TNF-α −308A/G polymorphism and −238A/G polymorphism were not associated with the risk of pneumonia in the overall population. In addition, TNF-α −308A/G polymorphism was not associated with pneumonia mortality. Future large sample size studies with more ethnic groups are needed to confirm our findings. Moreover, other TNF-α polymorphisms and gene-gene interactions should also be considered in future studies.In conclusion, our results suggested that


Toxocara infection in humans in Mexico has been poorly explored. There is a lack of information about Toxocara infection in waste pickers.The epidemiology of Toxocara infection in waste pickers.Determine the seroepidemiology of Toxocara IgG antibodies was determined in 90 waste pickers and 90 age- and gender-matched controls using an enzyme-linked immunoassay. Associations of Toxocara exposure with socio-demographic, work, clinical, and behavioral data of the waste pickers were also evaluated.Through a case control study design, the presence of anti-Toxocara IgG antibodies was significantly higher in waste pickers (12/90: 13%) than in control subjects (1/90: 1%) . The seroprevalence was not influenced by socio-demographic or work characteristics. In contrast, increased seroprevalence was found in waste pickers suffering from gastritis, and reflex and visual impairments. Multivariate analysis showed that Toxocara exposure was associated with a low frequency of eating out of home  and negatively associated with consumption of chicken meat . Other behavioral characteristics such as animal contacts or exposure to soil were not associated with Toxocara seropositivity.The seroprevalence of anti-Toxocara infection. 2) Toxocara is impacting the health of waste pickers. This is the first report of Toxocara exposure in waste pickers and of associations of gastritis and reflex impairment with Toxocara seropositivity. Results warrant for further research.1) Waste pickers are a risk group for  Toxocara is among the most common zoonotic infections worldwide Toxocara eggs are present in dogs and cat feces and become infectious within weeks after they are deposited in the local environment Toxocara larvae from undercooked giblets Toxocara are asymptomatic; however, Toxocara may lead to serious illness and death Toxocara infection in waste pickers. This group of population lives under disadvantaged socioeconomic conditions including poor housing, food, and sanitation, and has very low hygiene practices. In addition, waste pickers have not social security for covering health care services as diagnosis, treatment, and prevention of infectious diseases. This study was aimed to determine the seroprevalence of Toxocara infection in waste pickers in Durango, Mexico and to identify their characteristics associated with Toxocara seropositivity.Infection with the parasite Toxoplasma gondii serosurveys Toxocara IgG antibodies. Inclusion criteria for the waste pickers were: 1) waste pickers in the Municipal solid waste transfer station of Durango City, Mexico; 2) aged 14 years and older; 3) any gender; 4) waste picking for at least 3 months; and 5) who accepted to participate in the study. Waste pickers were 14–76 (mean  = 36.0+/−17.1) years old, 34 were males and 56 were females. Control subjects were matched with waste pickers by age and gender and consisted of 34 males and 56 females with miscellaneous occupations other than waste picking including students of public schools, employees, factory workers, housewives, business, and others. The mean age in controls was 35.7±16.8 (range: 18–78) years and comparable with that in waste pickers (P = NS).Through an age- and gender-matched case-control study using serum samples from recent This study was approved by the Ethical Committee of the Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado in Durango City. The purpose and procedures of the study were explained to all participants. A written informed consent was obtained from all participants.The characteristics of the participants were obtained by using a standardized questionnaire. Socio-demographic data including age, gender, birth place, residence, educational level, and socioeconomic level were obtained from all participants. Work characteristics included seniority in the activity, habitual use of safety practices (use of hand gloves and face masks), eating while working, drinking alcohol while waste picking, washing hands before eating, eating from the garbage, and ever had suffered from injuries with sharp material of the garbage. Clinical data explored included the presence of underlying diseases, memory, reflex, hearing, and visual impairments, and history of blood transfusion or transplants. Behavioral data included animal contacts, traveling, meat consumption , consumption of raw or undercooked meat, unpasteurized milk, dried or cured meat , consumption of unwashed raw vegetables, fruits, or untreated water, frequency of eating out of home (in restaurants or fast food outlets), contact with soil (gardening or agriculture), and types of floors at home from all participants were obtained.Toxocara IgG antibodies with a commercially available enzyme immunoassay “Toxocara” kit . Absorbance reading equal to or greater than 0.3 OD units was considered positive. All tests were performed following the instructions of the manufacturer.Serum samples were obtained from all participants and kept frozen at −20°C until analyzed. Serum samples were analyzed for anti-t test. Bivariate and multivariate analyses were used to assess the association between the characteristics of the waste pickers and Toxocara seropositivity. Variables were included in the multivariate analysis if they had a P value equal to or less than 0.20 in the bivariate analysis. Odd ratio (OR) and 95% confidence interval (CI) were calculated by multivariate analysis using multiple, unconditional logistic regression. A P value less than 0.05 was considered statistically significant.The statistical analysis was performed with the aid of the software Epi Info version 3.5.3 and SPSS version 15.0. The Pearson's chi-square test and the Fisher exact test  were used for comparison of the frequencies among groups. Age in cases and controls was compared with the student Toxocara IgG antibodies was significantly higher in waste pickers (12/90: 13%) than in control subjects (1/90: 1%) . General socio-demographic characteristics of the waste pickers studied are shown in Toxocara seroprevalence was not influenced by gender, age, residence, educational level, or socioeconomic status of waste pickers.The seroprevalence of anti-Toxocara seropositivity.None of the work characteristics in waste pickers including seniority in the activity, habitual use of safety practices, eating while working, drinking alcohol while waste picking, washing hands before eating, eating from the garbage, and ever had suffered from injuries with sharp material of the garbage influenced the prevalence of Toxocara seropositivity was significantly (P<0.05) higher in waste pickers suffering from gastritis and reflex impairment than those without such clinical features. Waste pickers with visual impairment had a higher (with borderline significance: P = 0.05) prevalence of Toxocara seropositivity than those without this clinical characteristic. The frequencies of other clinical characteristics including memory and hearing impairments, blood transfusion and transplant history were similar among Toxocara positive and Toxocara negative waste pickers.With respect to clinical data , the preP value equal to or less than 0.20 including: cats in the neighborhood (P = 0.07), traveling abroad (P = 0.09), consumption of pork (P = 0.13), beef (P = 0.12), chicken meat (P = 0.19), and raw goat milk (P = 0.04), and low frequency (up to 10 times a year) of eating out of home (P = 0.01). Other behavioral characteristics including raising dogs, soil contact, degree of meat cooking, or eating unwashed raw fruits and vegetables were not associated with Toxocara seropositivity in bivariate analysis. Multivariate analysis . In contrast, consumption of chicken meat was negatively associated with Toxocara exposure . No further behavioral characteristics of waste pickers associated with Toxocara exposure were found.Concerning behavioral characteristics , the bivanalysis  of the 7Toxocara IgG antibodies in waste pickers than in age- and gender-matched controls was found. Results clearly indicate that waste pickers represent a risk group for Toxocara infection. The 13% seroprevalence found in the present study indicates that Toxocara exposure is common among waste pickers; however, the lack of Toxocara seroprevalence studies in waste pickers does not allow comparing the prevalence of Toxocara seropositivity found with those in other waste pickers. However, in an international context, the seroprevalence in waste pickers is lower than those reported in some South American countries. Toxocara seroprevalences ranging from 21% to 39% have been reported in rural and urban populations in Bolivia Toxocara seroprevalences less than 5% reported in Canada Toxocara seroprevalence reported in Nepalese people In this study, a significantly higher seroprevalence of anti-Toxocara seroprevalence found in the present study was not significantly associated with any of the socio-demographic characteristics of the waste pickers. It has been reported that the prevalence of toxocariasis decreases with age Toxocara seroprevalence is waste pickers was not significantly influenced by age. This finding might suggest frequent Toxocara exposure in waste pickers. Toxocariasis has been associated with low educational level Concerning demographic characteristics, the Toxocara seropositivity and work characteristics were found. The lack of association of Toxocara seropositivity with the years of working suggests that Toxocara exposure might occur early during the waste picking activity.With respect to work characteristics, no significant associations of Toxocara infection is impacting the health of waste pickers. Firstly, the prevalence of Toxocara seropositivity was significantly (P<0.05) higher in waste pickers suffering from gastritis than those without such clinical feature. To my knowledge, there is not previous report of an association of Toxocara infection and gastritis. Further research on the role of Toxocara infection in gastritis is needed. Secondly, seroprevalence of Toxocara infection was higher (borderline significance: P = 0.05) in waste pickers with visual impairment than those without this clinical feature. Toxocara infection is a known cause of eye disease Toxocara seropositivity that those without this clinical feature. To my knowledge there is not previous report of an association of Toxocara seropositivity and reflex impairment. Infection with Toxocara may lead to neurological involvement Toxocara infection and reflex impairment is needed.Of the clinical data, results indicate that Toxocara seropositivity was associated with a low frequency of eating out of home. This result suggests that infection with Toxocara was not acquired in restaurants or fast food outlets. Instead, it is possible that Toxocara exposure in waste pickers might have occurred at the waste transfer unit or at home. In addition, multivariate analysis showed that Toxocara seropositivity was negatively associated with chicken meat consumption. This finding suggests that chicken meat did not play a major role in Toxocara exposure in waste pickers.Concerning behavioral characteristics, multivariate analysis showed that Toxocara seropositivity has been associated with dog ownership Toxocara seropositivity and dog or cat ownership was found. This finding agrees with those found in other studies Toxocara exposure and dog contact cannot be excluded because there were plenty dogs in the waste transfer unit and, therefore, waste pickers had contact with dogs at work. Contact with soil has been also found associated with toxocariasis Toxocara infection; 2) Toxocara is impacting the health of waste pickers. This is the first report of Toxocara infection in waste pickers and of associations of gastritis and reflex impairment with Toxocara seropositivity. Results warrant for further research.The conclusions of the present study are: 1) Waste pickers represent a risk group of


SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson’s patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson’s Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant . Our data also suggest a contribution to increased risk by the G-allele for rs356165 , and we observed a strong trend across categories when both genetic variants were considered (p for trend  = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.Currently, there are no reported genetic predictors of motor symptom progression in Parkinson’s disease (PD). In familial PD, disease severity is associated with higher α-synuclein ( Parkinson’s disease (PD) is a neurological condition characterized by progressive functional decline in motor function leading to disability and loss of quality of life There are only a few population-based (community) studies publishing on motor progression using multiple motor symptom assessments over time, i.e., with longitudinally followed PD patients Recent publications have called for prospective cohorts of PD patients assembled early in disease α-synuclein (SNCA) gene SNCA has been a candidate gene for idiopathic PD ever since the localization of the PARK1 loci to the SNCA gene region in a large Italian kindred SNCA is the microsatellite D4S3481 (SNCA-Rep1), located in the promoter, approximately 10 kb upstream of SNCA, and first reported in the Alzheimer literature SNCA-Rep1 Prior research has demonstrated a robust association between risk of PD occurrence and genetic variation in the SNCA suggests two distinct haplotype blocks, one covering an area from the 5′ end of the gene (the region of SNCA-Rep1) to exon 4 and the other covering from intron 4 to the 3′ region of the gene SNCA-Rep1 promoter variant in conjunction with other single nucleotide polymorphisms (SNPs) in the 5′ region SNCA-Rep1 has not yet demonstrated improvement in risk estimation SNCA most studies have investigated either rs356165  in a recent large study SNCA-Rep1 263bp allele arose on the haplotype background defined by the ‘G’ allele at rs356165 (or rs356219) thereby indicating a single genetic effect The linkage disequilibrium (LD) structure of SNCA 5′ and 3′ region genetic variants and age of onset of PD have been inconsistent SNCA possibly modifying the PD phenotype. Both SNCA-Rep1 SNCA gene, a known risk factor for PD onset, contributes to PD motor symptom decline.While findings from studies investigating This study was approved by the human subjects committee of the University of Los Angeles (UCLA). Subjects participated in the study after written informed consent was obtained; prospective participants and their families/guardians were asked to discuss the consent documents; consent on behalf of participants deemed incapable of consenting was obtained from those determined to be legal proxies for the patient.This longitudinal patient cohort is derived from a case-control study that enrolled PD patients and population-based controls between 2001 and 2007 in Central California. Recruitment methods SNCA genotype data available. All patients completed an interview to collect demographic and risk factor data; and provided blood samples for DNA.At first re-contact 83(22.9%) patients were deceased, 25(6.9%) withdrew, 9(2.5%) could not be found, and 4(1.1%) were too ill to participate. For follow-up, 242(66.6%) cases were successfully re-contacted with 6 patients participating by mail/phone only  and 3 patients re-classified by us during follow-up as not having idiopathic PD. Of 233 patients re-examined and confirmed to have idiopathic PD, 178(76.4%) were seen twice and 55 were seen only once during follow-up . For these analyses, 232 of the 233 patients with at least one follow-up had Baseline and follow-up Unified Parkinson’s Disease Rating Scale (UPDRS) SNCA genetic variants and rates of motor progression since our analyses would be too crude to predict actual levels of synuclein. Therefore, given that a 5 points/year change in motor UPDRS has been reported for early untreated PD patients in placebo arms of clinical trials Annual rate of change in UPDRS motor score was calculated as the difference of the last follow-up and the baseline motor scores divided by the interval of time (in years) between exams. We did not assume a linear association between the SNCA genetic variants were genotyped according to previously published methods SNCA microsatellite Rep1 (D4S3481) was genotyped using fluorescent-labeled forward and reverse primers designed to the α-synuclein promoter locus (accession no. U46895), Fam5′-CCT GGC ATA TTT GAT TGC AA-3′ and 5′-GAC TGG CCC AAG ATT AAC CA-3′. Detection and analysis was performed on an ABI 3730 DNA Analyzer  with Genemapper software. SNCA rs356165 in the 3′ untranslated region (3′UTR) was genotyped on an ABI 7900 Genome Analyzer using ABI Taqman® chemistry.Hardy-Weinberg equilibrium was assessed for each variant using Mendel 10.0 SNCA-Rep1 were analyzed in the manner originally presented by Maraganore et al SNCA SNP rs356165 was analyzed under an additive  genetic model similarly to prior studies SNCA-Rep1 and the 3′ rs356165 regions represent independent contributors to genetic risk of PD SNCA-Rep1 263bp allele and the rs356165 ‘G’ allele. P-values presented are uncorrected; for multiple comparisons considerations, four tests were performed and a p-value of 0.0125 was considered the experiment-wide significance level. Sensitivity analyses were performed to assess model robustness to additional possible covariates and the outcome cut-point.The repeat lengths of SNCA-Rep1 or rs356165 genetic variants  than non-carriers (67 years) at time of PD diagnosis, this difference was not formally statistically significant (p>0.10).The characteristics of PD patients in this report are summarized in variants . FinallySNCA-Rep1 259 allele and progression under a dominant genetic model although the odds ratio is in the expected (“protective”) direction  or 270% (two copies) under an additive genetic model . Finally, although we did not observe statistical interaction, patients with the ‘GG’ risk genotype at rs356165 and without the SNCA-Rep1 263bp risk allele exhibited a smaller increase in risk of faster progression than patients with the ‘GG’ risk genotype and with at least one copy of the SNCA-Rep1 263bp risk allele; additionally, we observed a strong trend across categories of the combined genetic variants  are correlated with SNCA mRNA expression in human postmortem brain tissues SNCA variants have functional consequences is accumulating rapidly. In our population-based idiopathic PD cohort, both the SNCA-Rep1 promoter and 3′UTR risk variants in combination with the promoter predicted faster motor symptom decline and these findings suggest that α-synuclein levels in idiopathic PD are strongly associated with progression as well as with disease risk.Apart from clinical trials of mostly younger onset patients SNCA Rep1 and rs356165 variants observed in our cohort of PD cases are very similar to those observed for PD cases in studies indexed by PDGene  is as expected in population based studies of PD; and similar to what was reported in the longitudinal study of incident PD in the UK  Consistent with observations from a recent longitudinal imaging study Rep1 263 = 4.05, 95%CI: 1.42–11.6).Due to the logistics of a population based study, we were unable to follow our patients on an annual or more regular basis, but our average annual rate of change measure accounts for differences in follow-up intervals. Moreover, our slow progressors were followed for a slightly longer interval thereby somewhat minimizing the extent to which slow progressing subjects were misclassified due to follow-up duration, since patients are less likely to improve once reaching a more advanced state of motor symptom decline. Finally, analysis limited to subjects with an interval from baseline to follow-up of 3 years or more (mean 5.82 years follow-up) produced odds ratios similar to analyses of the full sample .We lost a third of all patients between baseline and follow-up, mostly because participants had died. Other population-based studies of PD have similar or greater losses at follow-up: NY Unlike many longitudinal PD studies, we attempted to examine all patients in a practically defined off PD medication state, but this was not achieved in about 20% of exams. While this could have caused non-differential outcome misclassification with regard to genetic factors and an underestimation of the rate of progression and the effect size, we observed an overall mean change in UPDRS motor score of 2.52 points/year (average follow-up 5.1 years) which is very similar to the rate observed by the only other population-based incident study that estimated a mean change of 2.24 points/year (average follow-up 6.6 years) albeit this rate represents results from “on-on” exams Since motor symptom severity predicts increased mortality in PD independent of age and disease duration


N = 55,537 participants) were subjected to a multilevel meta-analysis. A mean small to moderate effect size was found (r = 0.18). Poor attachment to parents was significantly linked to delinquency in boys and girls. Stronger effect sizes were found for attachment to mothers than attachment to fathers. In addition, stronger effect sizes were found if the child and the parent had the same sex compared to cross-sex pairs of children and parents. Age of the participants moderated the link between attachment and delinquency: larger effect sizes were found in younger than in older participants. It can be concluded that attachment is associated with juvenile delinquency. Attachment could therefore be a target for intervention to reduce or prevent future delinquent behavior in juveniles.To investigate the link between attachment to parents and delinquency, and the potential moderating effects of age and sex, 74 published and unpublished manuscripts ( Poor attachment to parents is considered to be one of the causes of delinquency Bowlby . Althougindirect parental control: conventional behavior of the child is achieved as a by-product of strong child-parent attachments  and age differences (static versus dynamic theories). It may also provide starting points for developing or improving interventions for delinquent youth or children at risk for delinquency.The present meta-analytic study addresses the following research questions: Is poor attachment significantly associated with high levels of delinquency? How strong is the association between attachment and delinquency? Is age a moderator of the attachment-delinquency link? Is the association between attachment and delinquency moderated by sex of the child and the parent? We also test whether the attachment-delinquency link depends on the theoretical background of the study (control theory or attachment theory) and measure of attachment , and whether conceptual differences in attachment constructs  influence the relation between attachment and delinquency. Further, we examine moderator effects of methodological characteristics  in order to investigate potential influences of study quality on effect size. We also address the relative importance of the moderators and interaction effects of sex and age in a multivariate model.For the selection of studies four criteria were formulated. First, studies in which delinquency was defined as behavior prohibited by the law were selected. Studies that focused exclusively on problem behavior, which we consider as behavior that is not prohibited by the law, were not included. Second, studies had to focus on the quality of the attachment relationship, the bond to parents, or affectional identification, which considers both the child and the parent but not specific behavior of the child towards the parent or vice versa . If attachment was operationalized exclusively as behavior of the parent towards the child  the study was not selected. Also, studies on non-parent attachment relations such as attachments to peers were excluded. We collected empirical studies that tested assumptions from social control theory as well as from attachment theory. Third, samples would have to include participants from Western countries, because it is known that cultural differences exist with regard to child-rearing and attachment  and  and (parent*). After that, manual searches were applied, which means that reference lists of reviews and other articles were checked in order to find relevant studies not found in the electronic databases. We found 346 records in the databases of which we selected 137 on the basis of the information in the abstract. We finally found 74 manuscripts that met our criteria, which reported 151 analyses on the attachment-delinquency link. Findings of 63 independent studies that focused on a total of 55,537 subjects were reported.The tendency of journals to accept papers that report strong significant associations, referred to as publication bias, may have implications for the final conclusions of the meta-analysis  and sex of the parent . Given that unpublished studies are not verified by an outside public and are generally of poorer quality than published studies, we analyzed whether the quality influenced the combined effect size. We therefore gathered data on publication status  and some quality indicators from the empirical studies: sample size , design , source of delinquency . Finally, we collected data on ethnicity  because research has found this background variable to be linked to delinquency . Second, we collected data on the measure of attachment , because at least five very different methods of measuring attachment are used, including 1) observation, which is typically applied to collect information on attachment relations of infants  for parental control to 1.00 for publication status and gender of the child (both 100% agreement) and intraclass correlations ranging from 0.95 (70% agreement) for the effect size  to 1.00 for age at delinquency measurement (79% agreement), age at attachment measurement (85% agreement), ethnicity (91% agreement), and percentage of females (97% agreement).r to express the link between attachment and delinquency. We used the formulas of Mullen , indicating that youth with poor attachment relationships have higher levels of delinquency . Thus, although there was a significant association between most of the parenting variables and delinquency, this was not a consistent phenomenon. This suggests that study outcomes are likely influenced by study characteristics and justifies the investigation of potential moderators, which we report in the next subsections. The fail-safe number based on aggregated independent effect sizes  was 28,381. Given that the fail-safe number exceeded the critical value 5 k + 10, as suggested by Rosenthal , there was no indication of funnel plot asymmetry and therefore no indication of publication bias. These findings suggest that the mean effect size can be considered robust.The overall mean effect size for the association between attachment and delinquency was significant . With regard to the age of the subject at which delinquency data were collected we found a significant moderating effect. Studies that measured delinquency in younger participants resulted in larger effect sizes than studies in older participants . Thus, in general the link between attachment and delinquency becomes weaker as children age.We found a trend for the moderating effect of average r = 0.21 for mothers versus r = 0.19 for fathers; Z = -2.6, p < 0.01). Also, studies that focused on mothers alone yielded larger effect sizes than studies that focused on both parents or on ‘a parent’ . In order to analyze whether parents had more influence on a child with the same sex, we created a variable with the categories: (1) fathers - boys and mothers - girls, (2) fathers - girls and mothers -boys. The attachment-delinquency link was significantly stronger if parent and child had the same sex .Sex of the child did not moderate the attachment-delinquency association. . No significant interaction effects were found for age and sex of the child. With regard to the remaining moderators we found that sample size and study design was now nonsignificant in Model 2 and a trend was found toward an effect of ethnicity  were found Table . In the r = 0.18). This finding is relatively similar for studies examining the association between attachment and delinquency from the perspective of control theory and attachment theory.The present meta-analytic study summarizes and integrates previous findings on the link between attachment and delinquency, and examines factors that could have a moderating effect on this association, including age and sex. Results of this meta-analysis confirm previous findings in that poor attachment to parents is associated with more delinquent behavior. According to the criteria of Cohen  for smalTesting the potential effects of conceptual differences in attachment among studies revealed that not the theoretical background but the type of attachment measure moderated study outcomes. Studies that used parent reports and combined methods to measure attachment resulted in a relatively strong link between attachment and delinquency. This is consistent with findings of the meta-analysis by Fearon et al.  showing Second, some scholars have argued that the type of attachment measure can have an effect on the study outcomes, because different attachment instrument may measure different attachment concepts (Van IJzendoorn and Bakermans-Kranenburg r = 0.23), and psychological control  interventions for young delinquents or children at risk for delinquency, one should consider the attachment relationship with parents as a target of intervention. Next to insecure attachment or week bonds to parents these interventions should also aim to improve discipline techniques of parents.


Preeclampsia is a disorder characterised by vascular endothelial dysfunction and vasospasm that occurs after 20 weeks of gestation till 4–6 weeks postpartum. The global incidence of preeclampsia has been estimated at 2–14% of all pregnancies. Despite the advances made in the field, research is still organised to clarify the possible molecular mechanisms or predisposing factors of preeclampsia as well as the treatment options for such a significant disorder. Papers were selected on the basis of fundamental research ideas or reviews in the field. This special issue is comprising of seven papers which are focused on the better understanding of preeclapsia.One of the papers deals with the correlation of preeclampsia with hypoxia, thrombosis, and inflammation. The authors suggest that there is no accurate test for predicting preeclampsia. The role of markers such as sFLT, sEng, products of fetal and placental origin, markers of renal or endothelial damage, or markers of oxidative stress is presented by acting as secondary pathways to the pathophysiological changes that precede the clinical onset of preeclampsia. A combination of such markers is proposed in order to increase the detection accuracy earlier in the pregnancy and hopefully allow for more effective prophylactic strategies.Another paper sought to validate the use of urinary podocyte (podocyturia) as a single diagnostic marker in preeclampsia and in differentiating from other high-risk pregnancy states with similar presentations. The researchers discovered that podocyte loss is present not only in preeclampsia but in other high-risk pregnancy states. In addition, podocyturia was not found in a majority of patients diagnosed with preeclampsia. So, they realized that their findings had relatively low sensitivity and specificity, but they proposed further research regarding the predictive value of podocyturia in preeclampsia in larger studies.The authors of one of the paper investigated whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and preeclampsia in 236 pregnant women. They showed that there was significant difference in terms of genotype distribution between preeclampsia and controls, while it was not found any difference in allele frequency for ACE I/D polymorphism. A possible reason for the inconsistency could be the genetic basis that caused different susceptibilities among different populations.Moreover, one paper is mentioning that both women and children exposed to preeclampsia exhibit an adverse vascular phenotype, a propensity to subclinical atherosclerosis, and increased risk of adverse cardiac and vascular events in future life. They suggest that further studies into the mechanisms such as vascular dysfunction underlying the altered cardiovascular phenotype might provide unique insight into pathophysiological or molecular links between preeclampsia and cardiovascular disease which may direct us to novel treatment strategies for both conditions. Improvement in vascular function is also proposed as a valuable intermediate end point in studies aiming to reduce risk in this potentially young and generally asymptomatic population before the onset of clinical disease.F. J. Valenzuela and colleagues have recently reviewed some polymorphisms in important candidate genes involved in different pathogenic mechanisms related to preeclampsia and concluded that various studies in different populations have identified maternal polymorphisms associated with preeclampsia through candidate gene approaches.Luizon and colleagues with a Letter to the Editor add to the paper of F. J. Valenzuela et al. by further referring to candidate genes related to angiogenesis and endothelial dysfunction in preclampsia performed in the Brazilian population. Specifically, genotypes and haplotypes formed by polymorphisms of VEGF, eNOS, and MMP-9, along with an example of the interaction among these genes in the prediction of preeclampsia provide additional information with clinical relevance to its susceptibility.An additional paper is a review of the molecular mechanisms which are contributing to the pathogenesis of preeclampsia. Altered angiogenic balance, systemic inflammation, dysregulation of Renin-Angiotensin system, and placental hypoxia or ischemia are mechanisms leading to the pathogenesis of preeclampsia. However, it is unknown whether the mechanisms act independently or have synergistic effects.


Recently, genome-wide association studies have identified KCNQ1 as a type 2 diabetes (T2D) susceptibility gene in populations of Asian descent. After that, a number of studies reported that the rs2237892 and rs2237895 polymorphism in KCNQ1 has been implicated in T2D risk. However, studies on the association between these polymorphism and T2D remain conflicting. To investigate this inconsistency, we performed this meta-analysis.KCNQ1  encodes a pore-forming subunit of a voltage-gated KDatabases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Potential sources of heterogeneity were also assessed by subgroup analysis and meta-regression.A total of 25 articles involving 70,577 T2D cases and 99,068 controls were included. Overall, the summary odds ratio of C allele for T2D was 1.32  and 1.24  for KCNQ1 rs2237892 and rs2237895 polymorphisms, respectively. Significant results were also observed using co-dominant, dominant and recessive genetic models. After stratifying by ethnicity, sample size, and diagnostic criteria, significant associations were also obtained.This meta-analysis suggests that the rs2237892 and rs2237895 polymorphisms in KCNQ1 are associated with elevated type 2 diabetes susceptibility. Type 2 diabetes (T2D) is a complex metabolic disorder characterized by variable degrees of insulin resistance, impaired insulin secretion and elevated blood glucose. It has become a global major health problem showing worldwide increasing prevalence with an estimated 300 million people predicted to develop the disease by 2025 + channel (KvLQT1) that plays a key role for the repolarization of the cardiac action potential as well as water and salt transport in epithelial tissues Recently, spectacular advance was made in identifying susceptible genes involved in T2D through genome-wide association strategy (GWAS) KCNQ1 gene. Two polymorphisms (rs2237892 and rs2237895) which were in moderate linkage disequilibrium (LD) were first identified to be associated with increased T2D risk in Asians through genome wide association approach (r2 = 0.30) Several important single nucleotide polymorphisms (SNPs) have been identified in the KCNQ1 gene were identified through a search of PubMed, Web of Science, EMBASE and CNKI  with keywords “KQT-like subfamily, member 1”, “KCNQ1”, “type 2 diabetes mellitus”, “type 2 diabetes”, “T2D”, “T2DM”. All references cited in these studies and published reviews were examined in order to identify additional work. Eligible studies had to meet all of the following criteria: (a) should have been published in peer-reviewed journal; (b) were independent association studies investigating polymorphism with T2D using original data; (c) should have presented sufficient data to calculate the odds ratio (OR) with confidence interval (CI) and p value, and (d) should have described the genotyping method, equipment, and protocols used or provided reference to them. The major reasons for exclusion of studies were (a) overlapping data, (b) case-only studies and (c) review papers.Genetic association studies published before the end of June 2012 on T2D and polymorphisms in the Data extraction was performed independently by two reviewers and differences were resolved by further discussion among all authors. For each included study, the following information was extracted from each report according to a fixed protocol: first author, publication year, definition and numbers of cases and controls, diagnostic criterion, genotype frequency, source of controls, gender, body mass index (BMI), Hardy–Weinberg equilibrium (HWE) status, ethnicity and genotyping method.KCNQ1 and T2D risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (CI). The per-allele OR of the risk allele was compared between cases and controls using co-dominant genetic model. Additional pooled estimates were also given with corresponding results under co-dominant, dominant and recessive genetic models. Heterogeneity across individual studies was calculated using the Cochran’s X2 based Q-statistic test followed by subsidiary analysis or by random-effects regression models with restricted maximum likelihood estimation The strength of association between polymorphisms of The combined search yielded 85 references. 60 articles were excluded because they clearly did not meet the criteria or overlapping references . A totalP(Z)<10−5; P(Q)<10−5], with corresponding results under dominant and recessive genetic models of 1.62  and 1.40 , respectively. Similar results were also detected under co-dominant model  in large studies compared to 1.40  in small studies. In the stratified analysis by diagnostic criterion, significant associations were found for WHO criterion with per-allele OR of 1.31  and for ADA criterion of 1.38 . Subsidiary analyses of HWE status yielded a per-allele OR for controls consistent to HWE of 1.32 (95% CI: 1.27–1.38), while no significant results were detected for studies deviated from HWE. Similar results were also found using co-dominant, dominant or recessive genetic model , and South Asian . Similar significant associations were also observed for Caucasians . By considering sample size subgroups, the OR was 1.28 , mean age of cases (P = 0.11) and controls (P = 0.51), mean BMI of case (P = 0.65) and controls (P = 0.39), sex distribution in cases (P = 0.30) and controls (P = 0.38) did not significantly explained such heterogeneity. By contrast, ethnicity (P = 0.03) and sample size (P = 0.03) were significantly correlated with the magnitude of the genetic effect.Significant heterogeneity was present among the 36 data sets (P<0.05). In meta-regression analysis, diagnostic criterion . Significantly increased T2D risks were also found under dominant  and recessive  genetic model. Significant associations were also found using co-dominant model (For T2D risk and the rs2237895 polymorphism of nt model .−5) in small studies compared to 1.23  in large studies. Further stratified according diagnostic criterion, significant results were found for both WHO and ADA criterion in all genetic models . Similar results were also found in the Caucasian populations . Among South Asian populations, only marginally significant results were detected . In considering sample size subgroups, the OR was 1.29 , diagnostic criterion (P = 0.50), mean BMI of cases (P = 0.37) and controls (P = 0.26), mean age of cases (P = 0.05) and controls (P = 0.22), nor sex distribution in cases (P = 0.64) and controls (P = 0.61) were significantly correlated with the magnitude of the genetic effect; while ethnicity (P = 0.02) explained a large part of the heterogeneity.In meta-regression analysis, neither sample size (P = 0.12) and rs2237895 .A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data-set to the pooled ORs, and the corresponding pooled ORs were not qualitatively altered. The shape of the funnel plots was symmetrical for these polymorphisms  and S3. Multiple lines of evidence support an important role for genetics in determining risk for T2D. Two independent GWA studies recently performed in Japanese populations identified KCNQ1 as a T2D susceptibility gene Our results demonstrated that the C alleles of rs2237892 and rs2237895 polymorphism of KCNQ1 are a risk factor for developing T2D. In the stratified analysis by ethnicity, significant associations were observed among different populations in all genetic models among East Asian, Caucasian and South Asian populations, which suggested a similar role of the polymorphism in different ethnicity with different genetic backgrounds and living environment. Meta-analysis is often dominated by a few large studies, which markedly reduces the evidence from smaller studies. By considering sample size, significantly increased T2D susceptibility in KCNQ1 risk allele carriers was also found both in large and small studies for all genetic models. However, our results suggest an overestimation of the true genetic association by small studies. Besides, studies using different diagnostic criterion also get consistent positive results. Furthermore, we explored potential sources of heterogeneity across studies and the possibility of publication bias.V-channels are believed to play an important role in the pancreatic β-cells mediating repolarization of the membrane terminating Ca2+-influx and insulin secretion, and a KV-channel knock-out in rat islets as well as pharmacological inhibition of KV-channels in mouse β-cells have been reported to enhance glucose-stimulated insulin secretion V 7.1 channel, encoded by KCNQ1, is expressed in INS-1 cells and has been suggested to play an important role in maintaining the membrane potential in these cells The KAlthough it has been known for decades that both type 2 diabetes and obesity have a genetic basis Several potential limitations of the present meta-analysis should be taken into consideration. First, although the funnel plot and Egger’s test showed no publication bias and although an exhaustive literature search was done, it is likely that some publications and unpublished data were overlooked. Selection bias for the meta-analysis might have occurred. Second, our results were based on unadjusted estimates, whereas a more precise analysis could be conducted if all individual raw data were available, which would allow for the adjustment by other co-variables including age, drinking status, obesity, cigarette consumption, and other lifestyle factors. Third, lack of individual-level data prevent us from making further analysis to identify any interactions between genetic variation and metabolic traits .In summary, this meta-analysis showed that the KCNQ1 rs2237892 and rs2237895 polymorphism was significantly associated with increased risk of T2D. As studies among Middle East and African populations are currently limited, further studies including a wider spectrum of subjects to investigate the role of this locus in these populations will be needed. Moreover, gene–gene and gene–environment interactions should also be considered in future studies.Figure S1The flow chart of the included studies.(TIF)Click here for additional data file.Figure S2Begg’s funnel plot of KCNQ1 rs2237892 polymorphism and type 2 diabetes.(TIF)Click here for additional data file.Figure S3Begg’s funnel plot of KCNQ1 rs2237895 polymorphism and type 2 diabetes.(TIF)Click here for additional data file.Checklist S1(DOC)Click here for additional data file.