Objective: Many studies have focused on the association between the ABCB1 3435C>T polymorphism and colorectal cancer (CRC) risk. However, the results were conflicting. The aim of this meta-analysis is to evaluate the precise association between this polymorphism and CRC risk.Methods: We formally reviewed the literature at Pubmed, EMBASE and the Cochrane Library with the key words as follows: ABCB1/MDR1/P-glycoprotein, polymorphism, colorectal and cancer/neoplasm/tumor. This meta-analysis was assessed by Review manager 5.0. The fixed-effects model was used to pool the odds ratios (OR) with 95% confidence intervals (CI) for CRC risk.Results: There were 8 studies identified. The pooled OR with 95% CI of CC+CT versus TT genotype of the ABCB1 3435C>T polymorphism for CRC risk was 1.01 [0.90-1.13]. The sensitivity analysis further confirmed the result. Heterogeneity and publication bias were not observed in this meta-analysis.Conclusions: In summary, there was no significant association between the ABCB1 3435C>T polymorphism and CRC risk.Abbreviations used: the ATP-binding cassette, subfamily B, member 1 (ABCB1); multidrug resistance gene 1 (MDR1); P-glycoprotein (P-gp); colorectal cancer (CRC); single nucleotide polymorphisms (SNPs); odds ratio (OR); confidence interval (CI); Hardy-Weinberg equilibrium (HWE). In recent years, many studies have begun to recognize the importance of single nucleotide polymorphisms (SNPs) in genes that are involved in xenobiotic metabolism that might account for CRC risk. A number of common SNPs associated with CRC risk play a critical role in the development of CRC via modifying the expression of target genes that regulate cell behaviors.Colorectal cancer (CRC) is both the prevailing malignancy and one of the leading causes of cancer-related mortality in the Western World, with great impact on the life quality of affected persons.4 It is found that P-gp is highly expressed on the atypical surface of differentiated tubular structures in CRC and the expression of P-gp is associated with the progression of CRC.5,6 The ABCB1 gene is polymorphic and to date approximately 48 SNPs have been identified.7 SNPs probably change the functional expression of the ABCB1 gene so that predisposing to diseases.The ATP-binding cassette, subfamily B, member 1 (ABCB1), also named multidrug resistance gene 1 (MDR1), is located on chromosome 7q21.1. It encodes P-glycoprotein (P-gp) which is a 170kDa transmembrane transporter that acts as an ATP-dependent efflux pump of xenobiotics and various chemotherapeutic drugs. P-gp is expressed in normal cells of various organs such as intestine, liver, kidney, brain, and placenta, which is involved in absorption and elimination of xenobiotics and drugs and hence, could be a risk factor of diseases. On the other hand, P-gp probably also plays a role in regulating cell death, differentiation, and proliferation, as well as in immune response.8 There were studies focused on the ABCB1 3435C>T polymorphism, which had influence on inflammatory bowel disease risk rather than breast cancer risk.9,10 For CRC, some studies have reported a link between ABCB1 3435C>T polymorphism and CRC risk,11-14 while others have reported conflicting results.15-18 Hence, whether the ABCB1 3435C>T polymorphism is associated with CRC risk still remains controversial.The well-known ABCB1 gene polymorphism is 3435C>T polymorphism. The 3435C>T polymorphism in exon 26 is a synonymous C to T transformation, which encodes the amino acid isoleucine and probably affect the expression of ABCB1 gene and the function of P-gp in certain way.To resolve the dispute, we have presented a meta-analysis of the association between the ABCB1 3435C>T polymorphism and CRC risk.Study Selection: Search was applied to the following electronic databases: the Cochrane Library , Pubmed (1966 to February 2013) and EMBASE (1980 to February 2013). The following key words were used: “ABCB1 or MDR1 or P-glycoprotein”, “polymorphism”, “colorectal” and “cancer or neoplasm or tumor”. The research was conducted on human study, and non-English language studies were excluded. The reference lists of reviews and retrieved articles were hand searched at the same time. We did not consider abstracts, letters and unpublished studies. When more than one studies of the same population were identified, we included the study with the largest sample size. We reviewed abstracts of all citations and retrieved studies. For inclusion in this meta-analysis, the identified studies had to provide information on: (1) the number of CRC cases and controls studied; (2) the number of homozygous and heterozygous genotypes of ABCB1 3435C>T polymorphisms in cases and controls. Major reasons for exclusion of studies were: (1) no control; (2) duplicate; (3) no usable data reported.Data Extraction: All data were extracted independently by two reviewers (Dan Zhang and Cun Wang) according to the prespecified selection criteria. The following data were extracted: the first author’s surname, publication year, ethnicity, genotyping methods, number of cases and controls, number of genotyped cases and controls . Disagreement was resolved by discussion. If a consensus was not reached by discussion, a third party (Zongguang Zhou) was consulted to resolve the dispute.Statistic Analysis: The meta-analysis was performed by using Review manager 5.0, and p < 0.05 was considered statistically significant. The odds ratio (OR) with 95% confidence interval (CI) of CC+CT versus TT genotype of ABCB1 3435C>T polymorphism was pooled for CRC risk. Whether the distributions of genotypes among controls conformed to Hardy-Weinberg equilibrium (HWE) was determined by using a chi-square test and p < 0.05 was considered a departure from HWE. Statistical heterogeneity was measured by using I2 statistic and p < 0.05 was considered representative of significant statistical heterogeneity. Heterogeneity was also assessed through visual examination of funnel plots. Fixed effects model was used when there was no heterogeneity of the results of the studies. Otherwise, the random effects model was used. Sensitivity analysis was conducted by omitting each study.Characteristics of the included studies: There were 8 studies which met the inclusion criteria in this meta-analysis of 2996 cases and 3460 controls in Caucasian (n=7) and Asian (n=1), published between 2005 and 2011. The distributions of genotypes among controls of the whole studies conformed to HWE. The detailed characteristics of the studies included in our meta-analysis are presented in Association between ABCB1 3435C>T polymorphism and CRC risk: It is presented in 2=22%, P=0.26), which was also confirmed through the funnel plots in We performed a sensitivity analysis which is presented in This meta-analysis which included 2996 cases and 3460 controls, failed to show an association between ABCB1 3435C>T genotypes and CRC risk.19,20 P-gp was found on apical surfaces of superficial columnar epithelial cells of the colon at high concentrations.21 The proposed role of P-gp in the colon is to decrease the deposition of endogenous and exogenous hydrophobic amphipathic toxins5,22 Therefore, the decreased expression or lower activity of P-gp probably contributes to the increased risk of the colon diseases such as CRC and vice versa. Hoffmeyer et al. reported Caucasian individuals with homozygous TT genotype of ABCB1 3435C>T polymorphism had lower intestinal expression of P-gp and greater P-gp substrate digoxin absorption in the intestine after oral administration.8The ABCB1 gene mainly encodes a plasma membrane pump, P-gp, which protects the cells and organs against from toxic xenobiotic agents and environmental carcinogens by draining various structurally unrelated anticancer agents and toxins.23,24 Hitzl and Drescher et al. also reported Caucasian individuals with the homozygous TT genotype had lower mRNA level of ABCB1 and decreased function of P-gp.25,26 However, the controversy was caused by conflicting studies. Several studies reported Japanese individuals carrying T allele had greater mRNA level of ABCB1 and lower serum concentration of digoxin.27-30 Moreover, Siegmund et al. did not found any influence of ABCB1 3435C>T polymorphism on intestinal expression of P-gp and disposition of P-gp substrate talinolol in Caucasian.31 Several studies reported ABCB1 3435C>T polymorphism did not correlate with the expression and function of P-gp in acute myeloid leukemia, recipients of living-donor liver transplantation, peripheral blood lymphocyte and hematopoietic stem cells.32-35Verstuyft et al. and Johne et al. showed Caucasian individuals with the homozygous TT genotype had higher plasma concentration of digoxin as well.26,31,33,36-42 Possible explanations for those different results are that the 3435C>T polymorphism is a wobble SNP, which may not be the sole SNP affecting the expression of ABCB1 gene and there are the existence of gene-gene interaction and linkage disequilibrium between the 3435C>T polymorphism and other ABCB1 gene polymorphisms. Moreover, the expression of P-gp is probably different in different tissues and the methodology of measuring the expression of P-gp differs between studies. In addition, different substrates of which some are not only mediated by P-gp but also transported by other transmembrane proteins have been used in the various studies with different routes of administration. Thus, there is still no agreement about whether the ABCB1 3435C>T polymorphism has influence on the expression and function of P-gp.Furthermore, the conflicting data had been noted also for other P-gp substrates such as talinolol, fexofenadine, cyclosporine and tacrolimus.11 Sainz et al. also found Caucasian males with homozygous TT genotype had higher CRC risk than males carrying C allele.12 However, Andersen et al. found Caucasian individuals carrying T allele had lower CRC risk than those with homozygous CC genotype, and individuals with homozygous CC genotype who took red and processed meat were at 8% increased CRC risk.13Meanwhile, it also remains controversial that whether the ABCB1 3435C>T polymorphism is associated with CRC risk due to the different results of various studies. Kurzawski et al. reported Caucasian individuals under 50years of age with homozygous TT genotype had the highest CRC risk.14 Furthermore, several studies did not found association between ABCB1 3435C>T polymorphism and CRC risk.15-18 In addition, Indicibus et al. reported there was no association between the expression of P-gp and ABCB1 3435C>T polymorphism.18 The pooled result of this meta-analysis indicated that the homozygous TT genotype of ABCB1 3435C>T polymorphism probably not affect CRC risk. We speculated that ABCB1 3435C>T polymorphism, with other SNPs and factors of sex, age, or lifestyle, probably comes together or partially to affect CRC risk, or perhaps indeed not.Osswald et al. reported there was interaction between the combination of several ABCB1 polymorphisms including 3435C>T polymorphism and the status of smoking and age in relation to CRC risk.This meta-analysis is potentially limited in the following ways. First, it is difficult to avoid the selection bias since our search was restricted to studies reported in English. Second, not all controls of studies included in our meta-analysis were selected from predominantly healthy populations, and some might have had benign diseases. Therefore, the result should be interpreted with caution because the controls were not uniformly defined. We were also unable to perform subgroup analysis by ethnicity, because there was only one study of Asians and none of Africans. Finally, our meta-analysis was based on unadjusted estimates, and we were unable to perform more precise analysis to examine the interactions of SNPs, age, sex and lifestyle which might be important components of the association between the ABCB1 3435C>T polymorphism and CRC risk because of the lack of individual data.This meta-analysis provides further evidence that the ABCB1 gene has been highly investigated and plays important roles in CRC, but it is unlikely that the ABCB1 3435C>T polymorphism plays a major role in the etiology of CRC. Therefore, in this context, it is not recommended that individuals are tested for the ABCB1 3435C>T polymorphism as information which is useful in the diagnosis of CRC. Future prospective large well-design study should investigate the influence of the interaction of ABCB1 haplotypes and environment, rather than single SNP so that spurious correlation results are minimized.


Analyse the effect of the Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA), a wage-for-employment policy of the Indian Government, on infant malnutrition and delineate the pathways through which MGNREGA affects infant malnutrition. Hypothesis: MGNREGA could reduce infant malnutrition through positive effects on household food security and infant feeding.Participants: Infants aged 1 to <12 months and their mothers/caregivers. Final sample 528 households with 1056 participants, response rate 89.6%. Selected households were divided into MGNREGA-households and non-MGNREGA-households based on participation in MGNREGA between August-2010 and September-2011. Outcomes: Infant malnutrition measured using anthropometric indicators - underweight, stunting, and wasting (WHO criteria).Mixed methods using cross-sectional study and focus group discussions conducted in Dungarpur district, Rajasthan, India. We included 528 households with 1,056 participants. Out of 528, 281 households took part in MGNREGA between August’10, and September’11. Prevalence of wasting was 39%, stunting 24%, and underweight 50%. Households participating in MGNREGA were less likely to have wasted infants  and less likely to have underweight infants  than non-participating households. Stunting did not differ significantly between groups. We did 11 focus group discussions with 62 mothers. Although MGNREGA reduced starvation, it did not provide the desired benefits because of lower than standard wages and delayed payments. Results from path analysis did not support existence of an effect through household food security and infant feeding, but suggested a pathway of effect through low birth-weight.Participation in MGNREGA was associated with reduced infant malnutrition possibly mediated indirectly via improved birth-weight rather than by improved infant feeding. Addressing factors such as lack of mothers’ knowledge and inappropriate feeding practices, over and above the social and economic policies, is key in efforts to reduce infant malnutrition. In 2005–06, more than 40% of children in India were malnourished Ethics approvals for the study were obtained from the Directorate of Medical, Health and Family Welfare Services, Government of Rajasthan, Jaipur and the University of Oxford Tropical Research Ethics Committee (OXTREC); OXTREC Reference: 43-11. Participant information sheet and consent form in local languages were used to elicit written informed consent from all participants before implementing the survey questionnaire. Written informed consent was taken from the mothers of infants before measuring the weight and length of infants. Written informed consent was also taken from all participants before the focus group discussions.MGNREGA is a wage-for-employment policy that “provides 100 days of guaranteed wage-employment to rural households whose adult members volunteer to do unskilled manual work” MGNREGA is currently implemented in all districts in India, thus using an intervention trial to analyse its effect on infant malnutrition was not possible. The study was conducted in the Dungarpur district in the Indian state of Rajasthan where MGNREGA has been implemented since September, 2006. The degree of poverty and unemployment in the district alongside a high prevalence of malnutrition among children The target sample size of 540 households for the cross-sectional study was calculated assuming a two-sided, two-sample comparison of proportions. The assumed baseline prevalence of being malnourished was based on the reported prevalence of the anthropometric indicators - underweight 41.7%, wasting 19.2% and stunting 53.4% in children under 5 years of age in Dungarpur district Dungapur district is divided into five administrative blocks with 872 revenue villages in total. Each village was regarded as a cluster and 44 villages  were randomly selected using a single-stage cluster random sampling design. All households with infants aged 1 to <12 months  in each of these villages were invited to participate. Infants <1 month of age were not included in the study because access to them was difficult due to cultural beliefs that restrict outsiders from coming in contact with infants until 40–45 days after birth. In total 615 households were approached and the response rate was 89.6%. The selected households were divided into MGNREGA-households and non-MGNREGA-households based on participation in the MGNREGA between August-2010 and September-2011.A total of 551 households were surveyed with data collected on 1102 participants (551 pairs of mother and infant in each household). The survey questionnaire was administered face-to-face by MN and trained nurses to 551 mothers, and weight and recumbent length of 551 infants were measured. After excluding households with missing anthropometric data, 528 households with 1056 participants were included in the final analysis.The three traditional anthropometric indicators of malnutrition – wasting, stunting and underweight were used as outcome variables. Wasting (low weight-for-height/length) is an indicator of “current nutritional status” and is an established measure of acute malnutrition Household food security was measured using the standard Food and Nutrition Technical Assistance–2 (FANTA-2) household food insecurity indicator - Household Dietary Diversity Score Focus groups were used to generate themes and interactions through group discussion with the mothers of infants to explore the proposed mechanisms of effect of MGNREGA on infant malnutrition. A purposive sampling method based on mothers’ willingness to participate was used to recruit participants for eleven focus group discussions (two in each of the five administrative blocks and one pilot study). Participants comprised of 62 mothers of infants who were a sub-set of the randomly selected participants for the cross-sectional study (a nested sampling approach). The focus group discussions were conducted by MN with the help of a trained nurse using a semi-structured topic guide. The discussions were recorded, transcribed non-verbatim and translated into English. The transcripts were managed using the QSR International’s NVivo9 software and analysed using set and emergent themes.Descriptive analyses of all variables were conducted. Univariable logistic regression analyses were done for each of the three binary anthropometric outcomes – underweight, wasting and stunting to estimate the crude odds ratios. Since participation in MGNREGA was not randomised, exploratory logistic regression analysis was also used to identify the factors that influenced households’ participation in MGNREGA. These factors along with other known confounders were then entered into the multivariable logistic regression models to estimate the adjusted effects of households’ participation in MGNREGA on the anthropometric indicators of malnutrition. Tests for interaction were conducted to identify the factors that could modify the effect of MGNREGA on the outcome variables. To account for data dependency and within-cluster correlations, robust standard errors (Huber-White sandwich estimator) were reported.2) test for model fit, Comparative Fit Index (CFI) and Root Mean Square Error of Approximation (RMSEA), each related to a specific aspect of the model were used to quantify the degree of correspondence between the hypothesized models and the data Path analysis was performed to quantify the hypothetical pathways shown in  by fittiOf the total 528 households, 53%  = 48.9–57.5; n = 281) participated in MGNREGA. The overall prevalence of underweight, stunting and wasting among the infants in the study households was 50.4% (95% CI = 46.0–54.7), 24.4% (95% CI = 20.8–28.3) and 39% (95% CI = 34.8–43.3), respectively. The characteristics of the study population are presented in Further, the results of the exploratory logistic regression modelling conducted to elucidate systematic differences leading to MGNREGA participation and non-participation that may be brought about by factors such as socioeconomic status, belonging to below poverty line status, parents’ level of education, caste, household food security, households’ enrolment in Public Distribution system, primary occupation of the household and indicators for health seeking behaviour  suggested that only households categorised as being below the poverty line were more likely to participate in the programme . Apart from this no other known factor was found to be significantly associated with participation in MGNREGA.The adjusted odds of infants being underweight and wasted in households participating in MGNREGA were respectively 52%  and 43%  lower compared with households that did not participate in MGNREGA after controlling for socioeconomic status, below poverty line, caste, duration of care by other carers, birth order and child’s age . There wFour themes emerged from the focus group discussions to help explain the quantitative findings relating MGNREGA to infant malnutrition. These included the effect of MGNREGA on household food security, impact of poverty on infant feeding, mothers’ knowledge of infant feeding and cultural factors affecting infant feeding.Agriculture is the main source of livelihood in the district of Dungarpur. The participants suggested that earnings from MGNREGA contributed towards preventing hunger and starvation when there was crop failure particularly among the poor.“If there is no Rojgar Guarantee [MGNREGA] then what do we eat? If we get some money [we] can buy food grains for the house and [we] can go on. What ripens in cultivation? What do we eat? There are no crops, so we have benefited from Rojgar [MGNREGA].” (M-13)A participant employed through MGNREGA at the time of interview commented that if the programme was to be abolished, the poor people would be the losers because they do not have recourse to any other means of income. Although it was agreed that MGNREGA conferred some benefits in terms of preventing hunger during crop failure and meeting minor household expenses, the participants complained of low wages and delays in receiving payments. They did not trust the supervisors responsible for paying the wages to the workers, and commented that they siphoned off money and paid only a small portion of the daily wages to the workers. The participants perceived these as barriers to receiving the complete financial benefits from the programme.“Who gets 100 [INR]? The person responsible for paying us the wages takes away most of it. Last time I got 200 rupees for 11 days.” (M-19)roti (bread) made of either wheat or maize. Although the mothers were aware that these foods could harm the child, they could not afford to buy anything else. For example, a mother mentioned that her young daughter was unable to swallow dry bread and often vomited it out, so she had no option other than breastfeeding.Poverty itself was a factor that negatively affected infant feeding. “Inability to afford” compromised the type of complementary foods given to the infants. These were mostly biscuits or a piece of dry ghee (clarified butter) to infants <6 months.Mothers’ knowledge of initiation of breastfeeding, exclusive breastfeeding and weaning appeared to be inadequate. There were several misconceptions such as breast milk is produced only after two hours of delivery of the child, and inappropriate practices such as giving water and animal milk  with or without “I started breastfeeding after 2 hours because I did not have enough milk. Milk comes only after 2 hours.” (M-40)In addition to poverty, cultural practices appeared to inform mothers’ knowledge and influenced the infant feeding practices. Apart from initiation of breastfeeding and exclusive breastfeeding, the time of initiation of complementary feeding and the type of food given was also determined by social customs.“We have this custom, Mama [maternal uncle] will give food to the child, rice, in 8th month or 9th month or 11th month. There is a puja [worship God] and then rice is given to the child.” (M-51)a priori that MGNREGA will affect infant malnutrition through improving household food security and via this improve infant feeding and birth weight  . HoweverUnlike the poor–MGNREGA model, neither the direct nor the indirect estimated effects of MGNREGA were found to be statistically significant in the non-poor-MGNREGA model . HoweverAs shown in Among our study population in Dungarpur, Rajasthan, MGNREGA had a significant effect on reducing wasting and underweight among infants in households that participated in MGNREGA compared with households that did not. The only other study that assessed the effect of MGNREGA on child malnutrition showed a negative effect on stunting, but not on underweight and did not provide estimates for wasting The findings of the focus group discussions suggested that although MGNREGA may help avoid starvation, lower than standard wages and delayed payments meant that the participants did not receive all the benefits of the programme. Several studies and programme audit reports have identified such problems related to wages and timely payments, a majority of which were attributed to corruption In our study, the economic benefits of participating in MGNREGA appear to be short term which helps to prevent acute malnutrition, but insufficient to have an effect on chronic malnutrition. This argument is supported by our finding that the effect on the anthropometric indicators of malnutrition did not vary with the number of years of participation of the households in MGNREGA. Further, the findings of the focus group discussions suggested that although MGNREGA was able to prevent hunger, the earnings were inadequate to confer household food security. Even if food security was obtained, this is unlikely to translate into adequate infant feeding because of lack of appropriate knowledge about infant feeding among the mothers in the study population. Cultural practices, societal norms and poverty played an important role in influencing mothers’ knowledge and practices. Other studies in different parts of India have also highlighted the problem of inadequate knowledge among mothers and the misconceptions prevalent with regards to infant feeding and care The path-models also provide an understanding of the role of the socioeconomic context in determining the effects of MGNREGA. MGNREGA is probably able to fulfil the basic nutritional requirements of pregnant women thereby reducing low birth-weight among infants in participating households compared with non-participating households in the poor socio-economic group. However, MGNREGA was not found to be effective in reducing malnutrition among infants in the comparatively better-off households. Although the results of path-analyses rely on the assumption of “no unmeasured confounding”, these are not causal models. Nevertheless, the results could have important implications for programme targeting.Cross-sectional studies provide a snap-shot of a point in time and the anthropometric indicators fluctuate across infancy and childhood, however, the magnitude of the logistic regression results suggest that the observed findings provide reasonable evidence. Considering that MGNREGA-households were comparatively poor , the logistic regression and path analysis results of protective effect of MGNREGA against malnutrition could not have been overestimated. Participation in MGNREGA is through self-selection and the exploratory regression analysis identified below poverty line status to be associated with household’s participation in MGNREGA in the study population. Although this factor was accounted for in the multivariable models, there could be other unknown factors that influenced participation in MGNREGA, thus selection bias cannot be completely ruled out. Further, despite adjusting for all known confounders identified from literature, there could still be residual confounding by unknown confounders.While the path-analyses controlled for a few determinants of low birth-weight  data on other important factors such as pre-pregnancy maternal nutrition and height, obstetric history such as age at first pregnancy, inter-pregnancy intervals etc. were not available. Since the study hypothesis was concerned with child related factors, data on the maternal factors were not collected. Including these factors in the model could alter the magnitude, strength and the direction of impact of MGNREGA on low birth-weight and thereby on infant malnutrition. Nevertheless, the study generates an important hypothesis about the positive effect of MGNREGA on infant nutrition through a maternal pathway which could be further explored in subsequent studies.This study is the first we know of to analyse the effect and the pathways of effect of MGNREGA on infant malnutrition and empirically demonstrates the inter-play of the various determinants of malnutrition. However, further studies are required to measure the effect of MGNREGA on infant and child malnutrition in different social, economic and geographical settings in India and also to delineate the observed maternal pathway. Ensuring timely and adequate payment could improve food security, and augment the protective effect of the MGNREGA. Factors such as lack of mothers’ knowledge about feeding and cultural practices related to inappropriate feeding are important risk factors of infant malnutrition. Identifying and addressing such factors, over and above the social and economic policies, is key in efforts to reduce malnutrition among infants. Therefore, policies need to focus on these factors and target the persistent problem of malnutrition prevalent in India through a convergence of development, health and nutrition policies and programmes.


Background: The angiotensin converting enzyme 2 (ACE2) G8790A gene polymorphism has been associated with the susceptibility to essential hypertension (EH), but the results are disputable. Objective and Methods: To investigate the relationship between the ACE2 G8790A gene polymorphism and EH, eight separate studies with 5260 subjects were meta-analyzed. The pooled odds ratio (OR) and its corresponding 95% confidence interval (CI) were calculated by a random effect model. Results: In the ACE2 G8790A gene polymorphism and EH meta-analysis in a Chinese population, no significant association was found between the ACE2 G8790A gene polymorphism and EH . In the stratified analysis by gender, no significant risk was found among males  or females . Under a dominant model of inheritance in the female subgroup, the pooled OR for the GG/GA + AA value was 1.01 . Under a recessive model of inheritance in the female subgroup, the pooled OR for the AA/AG + GG value was 0.93 . Conclusion: The current meta-analysis suggested that the ACE2 G8790A gene polymorphism might not be related to the increased EH risk in the Chinese population. ACE2, a homolog of ACE discovered by Donoghue et al.  I and generates Ang 1–9. Ang 1–9 is resolved into Ang 1–7, whose physiological activities are contrary to Ang II. Ang 1–7 can relax vessels, decrease the blood pressure, as well as inhibit the proliferation of cardiac myocytes, myocardium fibroblasts, and vascular smooth muscle cells. Hence, ACE2 and ACE exhibit mutual antagonism. ACE2 is supposed to demonstrate a protective function in the regulation of heart and blood pressures. Consequently, ACE2 may become a new treatment target for cardiovascular diseases.The gene polymorphism of e et al.  and Tipne et al. , has a cAngiotensin converting enzyme 2 gene, located in X chromosome, spans ∼2.4 kb and contains 18 exons. The G8790A polymorphism was at fourth base in the third intron adjacent to exon. The 8790th base guanine (G) was substituted by adenine (A) which resulted in the mRNA montage changes and ACE2 gene expression.ACE2 G8790A gene polymorphism with EH significantly differed among various ethnicities. Benjafield et al.  the EH diagnosis was in line with the 1999 EH diagnosis criteria of the World Health Organization as systolic blood pressure (SBP) ≥140 mmHg, DBP ≥90 mmHg. Secondary hypertension was not included in the present investigation.The inclusion criteria were as follow: (a) evaluation of the association between the ACE2 is located in the X chromosome, the meta-analysis was classified into male and female subgroups.Data were collected according to a standard protocol. Repeated publications, those that violate any inclusion criterion, and/or those deviating from the Hardy–Weinberg equilibrium (HWE) were excluded. If different articles conveyed the same results, the results were considered only once in the current meta-analysis. The information extracted from literature included the name of the first author, year of publication, region, number of genotypes, total number of cases, and controls listed in Tables ACE2 G8790A gene polymorphism and EH was assessed by the odds ratio (OR) corresponding to a 95% confidence interval (CI). The chi-square-based Q-test was used to check the heterogeneity assumption . The potential publication bias was estimated by the funnel plot. Egger et al.’s (P < 0.05) was used to assess the funnel plot asymmetry. The STATA 10.0 software  was used to perform all statistical analyses.The strength of association between the et al.’s  linear rA total of 15 papers were retrieved by the literature search, and eight of the papers fitted the study selection criteria. Of the seven excluded studies, three papers were reviews, three had nothing about the ACE 2 G8790A gene polymorphism, and one was a repeated publication , but the EH and control groups did not , but the EH and control groups did not , as shown in Figure P = 0.02, I2 = 69.2%), but the EH and control groups did not , as shown in Figure Pheterogeneity = 0.11, I2 = 50.7%). The association between the ACE2 G8790A gene polymorphism and EH in the women was not significant . There was no significant association between the ACE2 G8790A gene polymorphism and EH in the women , but publication year was the most important , and G genotype number of control group sample size (G0). All these confounding factors could explain the heterogeneity . In Subsection 2 of three studies, the pooled OR was 0.74 . The subsection analysis indicated that the heterogeneity in Subsection 2 was higher than that in Subsection 1. Therefore, studies on Subsection 2 need further improvement .No visual evidence of publication bias was found from the funnel plot Figure . There wACE2 does not affect blood pressure regulation, the serum Ang II level significantly increases. The cardiovascular and renal effects of Ang II are the most important long-term blood pressure regulation mechanisms. They have also found that ACE2 knockout mice exhibit the cardiac abnormalities similar with cardiac stunning in humans.Essential hypertension is a complex disease caused by a combination of genetic and environmental factors. Crackower et al.  have fouACE2 is the restriction enzyme cutting site located on the fourth base of the third intron. The code is ranked as rs2285666 in the United States Biotechnology Information Center. mRNA and protein expression levels change in cardiovascular diseases and diabetes mellitus (DM; Ribeiro-Oliveira et al., ACE2 gene expression. The latter led to changes in the serum content of Ang 1–7 that inhibited vasoconstriction and cell proliferation (Kramkowski et al., The G8790A gene polymorphism of ACE2 gene in X chromosomes, the association of the G8790A gene polymorphism and EH was classified and analyzed according to gender. In the present meta-analysis, under the premise that age and gender factors were controlled, no significant association was found between the ACE2 G8790A gene polymorphism and EH under allelic, dominant, and recessive genetic models. There was no significant difference between the EH and control groups in either male or female subgroups. The current meta-analysis suggested that the A allele of the ACE2 G8790A gene polymorphism might not be related to increased risk for EH.Given the location of the In the meta-regression of the confounding factor, the publication year was considered as the most important heterogeneity source. The publication year before 2007 indicated lower heterogeneity, and suggested that the early studies have the smaller heterogeneity than the latter studies.ACE2 G8790A gene polymorphism and EH in a Chinese Han population. The ACE2 G8790A gene polymorphism might not be a genetic risk factor for EH in the said population. However, not all of the included studies have followed the HWE. For instance, the study of Liu et al. (The results of the current research conformed to those of Zhou and Yang  who metau et al.  has deviu et al.  work, thu et al. . Moreoveu et al. . Given tACE2 G8790A gene polymorphism was not associated with susceptibility to EH in the Chinese population. Further studies should use higher investigation sample sizes. Given the relatively small sample size used in the present study, further research should be performed to test the abovementioned conclusion.In conclusion, the current meta-analysis suggested that the The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.http://www.frontiersin.org/Vascular_Physiology/10.3389/fphys.2012.00364/abstractThe Supplementary Material for this article can be found online at Supplementary Table S1Characteristics of the investigated studies of the association between the ACE2 G8790A gene polymorphism and EH of the male subgroup.Click here for additional data file.Supplementary Table S2RT-PCR primers utilized for each gene in the RT-PCR analysis.Click here for additional data file.


Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC).We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subject's neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC , while in the study using hospital controls, this was not the case . Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure.Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies. Although esophageal cancer ranks 8Defining an appropriate sampling frame from which controls should be selected is arguably one of the most difficult tasks in designing a case-control study. The aim is to select a group of controls which are representative of the community from which cases have been selected. In their review of the methodological issues of case-control studies, Wacholder and colleagues have stressed the importance of study base and control selection in case-control studies, and discussed several sources for control selection, including population controls, hospital or disease registry controls, controls from a medical practice, friend controls, relative controls, controls selected from case series, proxy respondents and deceased controls The Golestan Case-Control Study in northeastern Iran was carried out in two phases. In the pilot phase of the study, 130 incident esophageal squamous cell carcinomas (ESCCs) and 260 matched hospital controls were enrolled, while in the main phase of the study, 300 ESCC cases and 571 matched neighborhood controls were recruited The study was approved by the Institutional Review Boards of the Digestive Disease Research Center of Tehran University of Medical Sciences and the US National Cancer Institute.This study compares results from the pilot phase (March 2002–November 2003) and the main phase (December 2004–June 2007) of the Golestan Case-Control Study. Case selection and procedures in the pilot phase and the main phase of the study were the same. A detailed description of the case selection procedures has been published Hospitalized subjects were individually matched to each case on age and sex. Because tobacco use, alcohol consumption, and diet are thought to be important risk factors for ESCC Neighborhood controls were selected using the Iranian Family Health Census as the sampling frame. Two subjects were matched to each case by place of residence (urban neighborhood or village), age (±2 years), and sex. The interview team identified all of the potentially eligible controls in the case's village or urban area, and randomly selected two subjects to interview. If either of the selected controls could not be interviewed for any reason, another person on the list was randomly invited, and so forth. The total number of enrolled neighborhood controls was 571. Of the enrolled neighborhood controls 77% were the first randomly selected subjects, 11% were the second, and the remainder required more than two selections. In nearly all instances the reason that an eligible control did not participate in the study was the absence of the control at the time of invitation After obtaining written informed consent, a structured questionnaire with closed questions and pre-categorized responses was administered to both cases and controls by physician-researchers from Atrak Clinic. The questionnaire included detailed information on demographics, family history of cancer, history of tobacco, opium and alcohol use, drinking tea habits, oral health, and socioeconomic variables. More detailed information on the questionnaire is available elsewhere Univariate and multiple variable conditional logistic regression models were used to measure crude and adjusted odds ratios (OR) and 95% confidence Intervals (CI). In addition to the matching factors of age, sex, and place of residence, we also adjusted for education (as a determinant of socioeconomic status), ethnicity (Turkmen versus non-Turkmen) and consumption of cigarette, hookah, Nass and opium . We chose two previously identified risk factors for ESCC for comparing the two studies, use of different forms of tobacco and use of opium. We calculated the p-value of the heterogeneity test for each set of adjusted ORs. For significant differences between the two sets of controls, we also compared data from our two controls series with the data from the Golestan Cohort Study, a large cohort study conducted in the same geographic area A total of 130 ESCC cases and 260 hospital-based controls were enrolled in the pilot phase of the study, while the corresponding numbers of cases and neighborhood controls in the main phase of the study were 300 and 571, respectively. Demographic characteristics of the studies participants are shown in Distributions of age, ethnicity, and place of residence were similar between the cases in the two studies, but hospital-based controls were more likely to be non-Turkmen and live in the urban areas than the cases or the neighborhood controls., , , , Table 3 shows the results for Nass use. The results were nearly identical in the two studies. Approximately 8 to 9% of the controls used Nass in each study, and in both, the adjusted ORs show that Nass use was associated with a 1.5–1.8-fold increased risk of ESCC.The results for hookah are shown in Calculated standardized opium consumption prevalence's were 0.17, 0.16 and 0.23 for the cohort subjects, the neighbourhood controls and the hospital controls, respectively. We also pooled the data of the 430 cases from the two phases of the study and compared this pooled case data with that of the neighborhood controls and the hospital based controls separately, using non-conditional logistic regression. The results showed that in the analysis of the 430 cases and 570 neighbourhood controls, after adjusting for the confounding factors, using opium had a significant association with ESCC  while in the analysis of the 430 cases and 260 hospital controls, it did not .In this study, we compared the associations of tobacco-related variables and opium use with ESCC risk in two phases of a case-control study in the same population, one phase using hospital controls and one using neighbourhood controls. We found that the results were similar for cigarette smoking and Nass consumption in the two phases of study; both showed a similar magnitude of increased ESCC risk. It was difficult to compare the results for hookah use, as the prevalence of consumption in the study area is very low and our sample size was modest. We found a notable difference between the pilot and main phase results, however, when examining the effect of opium use. Compared to the neighbourhood controls, hospital-based controls were more likely to use opium, at rates close to those seen in cases. Therefore, while the neighborhood-based study showed an increased risk of ESCC with opium use, the hospital-based study did not.Whether hospital-based or population-based controls better satisfy the comparability criteria has been long debated in epidemiologic texts and articles In the current study, the prevalence of smoking among the hospital controls was close to that of the neighborhood controls, and also close to that found in the pilot phase of the Golestan Cohort Study in the same population Use of Nass in the hospital and neighborhood controls was also similar, but it was higher than what was found in the pilot phase of the Golestan Cohort Study pilot phase of the cohort study (19). However, we should not expect that the prevalence in the case-control and cohort studies should be similar, since Nass use is a function of sex, age, and ethnicity (it is most commonly seen in Turkmen men), and the case-control and cohort studies were dissimilar in these demographic variables.The pattern of association with hookah use was reasonably similar in the two phases of the study. However, as we mentioned above, the number of people who used hookah was very small, so it is difficult to draw any meaningful conclusions.The main difference between two studies was related to the association of opium consumption and ESCC risk. The cases in both studies had similar rates of opium consumption, but the hospital controls reported a higher prevalence of opium use than the neighborhood controls. So OR for opium use in neighbourhood control set is significant while it is not statistically significant in hospital control set and although test of heterogeneity was not significant, considering that the power of analysis in interaction test is not high enough we think that P value of 0.15 can be an issue for discussion.There are several potential explanations for this difference in prevalence among these two control groups. Hospital controls may not be representative of the population because in this area opium has traditionally been used to treat pain and numerous ailments, including those which brought some of these controls to the hospital. In addition, a recent study has shown that regular users of opium are more prone to accidents We compared standardized rates of opium use among the two sets of controls in the current study and the participants in the Golestan Cohort Study, which is the most representative survey that we have of the community from which the cases were selected, and we found that the prevalence of opium use in the cohort was much closer to that in the neighbourhood controls than it was to the prevalence of opium use in the hospital controls. This suggests that the neighbourhood controls were more representative of the study base than the hospital controls, at least for opium exposure. On the other hand, one might argue that the reported rates of opium consumption among neighborhood controls and participants in the cohort are lower than the real rates because they are not questioned in a medical setting and when they are sick, so they may not answer the questions as truthfully, and this may result in information bias. However, a recent study by our group showed that the responses given to the questions in the pilot phase of the cohort study, also in a non-medical setting, were very close to the results found by testing urine for markers of codeine and morphine This study has several strengths and limitations. Notable strengths, especially for the comparisons in this paper, were the high participation rates of both hospital and neighbourhood controls and the fact that the same team members interviewed all the cases and controls in both studies. One of the limitations is the modest sample size of the hospital-based study. Another is the fact that we cannot exclude the possibility that some of the exposures under study (particularly opium use) might be associated with the reasons that the hospital controls were hospitalized.In summary, the results of this study show that neighbourhood controls were superior to hospital controls in assessing the risk of ESCC associated with opium exposure in this population. But, as shown in this and other studies, both hospital and neighbourhood controls can bring biases into an evaluation. Optimal control group selection requires considerable thought, and the best control group may be different in different studies.


Structural, neurochemical, and functional abnormalities have been identified inthe brains of individuals with bipolar disorder, including in key brainstructures implicated in postural control, i.e. the cerebellum, brainstem, andbasal ganglia. Given these findings, we tested the hypothesis that posturalcontrol deficits are present in individuals with bipolar disorder. Sixteenparticipants with bipolar disorder (BD) and 16 age-matched non-psychiatrichealthy controls were asked to stand as still as possible on a force platformfor 2 minutes under 4 conditions: (1) eyes open-open base; (2) eyes closed-openbase; (3) eyes open-closed base; and (4) eyes closed-closed base. Postural swaydata were submitted to conventional quantitative analyses of the magnitude ofsway area using the center of pressure measurement. In addition, data weresubmitted to detrended fluctuation analysis, a nonlinear dynamical systemsanalytic technique that measures complexity of a time-series, on both theanterior-posterior and medio-lateral directions. The bipolar disorder group hadincreased sway area, indicative of reduced postural control. Decreasedcomplexity in the medio-lateral direction was also observed for the bipolardisorder group, suggesting both a reduction in dynamic range available to themfor postural control, and that their postural corrections were primarilydominated by longer time-scales. On both of these measures, significantinteractions between diagnostic group and visual condition were also observed,suggesting that the BD participants were impaired in their ability to makecorrections to their sway pattern when no visual information was available.Greater sway magnitude and reduced complexity suggest that individuals withbipolar disorder have deficits in sensorimotor integration and a reduced rangeof timescales available on which to make postural corrections. Although the nature and origins of bipolar disorder (BD) are still relatively poorlyunderstood, abnormalities in diverse brain regions have been identified. Behavioral,structural, and diffusion tensor imaging studies provide convergent evidence ofanterior limbic network abnormalities in BD, and the pattern of emotional andcognitive deficits observed in BD is consistent with abnormalities in acerebello-striatal-prefrontal circuit An emerging literature suggests motor abnormalities accompany mood and psychoticsymptoms of BD, although the relationship between motor and mood disorders hasrarely been studied explicitly Importantly, the brain areas that participate in mood regulation and have been foundto be abnormal in BD also play critical roles in motor function. For example, thecerebellum is a key structure in motor control and plays an integral role in theproduction of smooth, coordinated movement and in maintaining postural controlthrough appropriately timed activation of agonist and antagonist muscles. Morerecently, empirical and theoretical evidence have indicated that the cerebellumplays a significant role in psychological functions as well, including modulation ofperceptual, cognitive, and affective functions The basal ganglia also play a crucial role in motor behavior and show abnormalitiesin BD. This brain circuit is crucial for the initiation of movement and plays animportant role in multisensory integration, especially proprioceptive-motorintegration Finally, the brainstem is also critically involved in motor function, and isparticularly involved in the coordination of vestibular and visual input withafferent proprioceptive information Postural sway is a sensitive test of the integrity of motor control that is likely tobe affected by abnormal or aberrant functioning of the cerebellum, basal ganglia,and brainstem. Given evidence of abnormalities in the aforementioned brain circuitsin bipolar disorder, the present study tested the hypothesis that BD patientsexhibit increased postural sway, indicative of poorer postural regulation, relativeto a healthy control group. The second goal of this research was to test thehypothesis that the dynamic properties of movement as it evolves over time are alsoabnormal in BD. To examine the processes generating the sway pattern, dynamicanalyses were applied In order to examine the amount and dynamic pattern of postural sway in participantswith BD, four different postural conditions that alter the availability ofproprioceptive (closed vs. open base stance) and visual (eyes open vs. eyes closed)information were employed. Proprioceptive, vestibular, and visual inputs affectdifferent time-scales contributing to the correction of postural stability andremoval of any one of these components cause increases in sway area Finally, although sway area generally can be expected to increase with the removal ofsensorimotor input, the alterations in the complexity of sway dynamics caused bymanipulations of either proprioceptive or visual input in non-clinical populationsare not identical. For example, the proprioceptive feedback loop works along muchshort time-scales The study procedures were approved by the Indiana University-Purdue UniversityIndianapolis Institutional Review Board and the study was conducted inaccordance with the Declaration of Helsinki (Edinburgh amendments). Writteninformed consent was obtained from all participants.2(1) = 0.50, p = ns).Diagnostic status was determined using the Structured Clinical Interview forDSM-IV Axis I Disorders (SCID-I) Participants included in the analyses were 16 individuals (7 women) with DSM-IVbipolar disorder (BD) and 16 age-matched non-psychiatric healthy controls (9women). A boxplot method of outlier identification was used to classify extreme data values separately for each analysis. Extremeoutliers were defined as data values>6 quartiles from the upper or lower endsof the inter-quartile range. Following age-matching, there were initially 18participants in each group, but one BP and one control were removed from theanalysis due to classification as extreme outliers in at least one COPcondition. All demographic and statistical information is reported for theremaining 16 participants in each group. Gender did not differ between groups didnot differ from controls ,t(30) = −0.07, p = ns. Body massindex (BMI) of BD participants  and controls  also did not statistically differ,t(30) = −0.16, p = ns. Inclusioncriteria were completion of grade school level education, normal or corrected tonormal hearing and vision, no history of cardiovascular or neurological disease,body mass index of less than 40, and no history of head injury that resulted inloss of consciousness. All BD participants were euthymic, with mean YMRS scoresof 4.6 (SD = 5.1) and MADRS scores of 4.2(SD = 4.7). Finally, BD participants had been assessedwithin the previous 2 weeks using the Abnormal Involuntary Movement Scale (AIMS)Four individuals with bipolar disorder were un-medicated at the time of testing.The remaining 12 were on various combinations of psychotropic medications, whichare listed for each individual in Each participant was required to stand as still as possible while barefoot on anAMTI Accusway  force platform under the following taskconditions: (1) eyes open-open base; (2) eyes closed-open base; (3) eyesopen-closed base; and (4) eyes closed-closed base. During the open baseconditions, feet were placed shoulder width apart; participants stood with theirfeet together (approximately 1 inch apart) during the closed base conditions.Each trial lasted 2 minutes.The center of pressure (COP) motion along the anterior-posterior andmedio-lateral axes of motion were obtained from the force platform, sampled at arate of 50 Hz and filtered with a 9th order Butterworth low-pass filter with a25 Hz cutoff frequency to isolate the low-frequency postural sway process. Swayarea was measured during each trial to provide the amount of sway for eachparticipant during each condition. Postural sway signals have time-varyingstatistical properties f noise andcharacterizes fractals and healthy physiological systems, indicating the maximumdegree of self-similarity in a signal In order to assess the more complex dynamics of postural sway, detrendedfluctuation analysis (DFA) was performed on the COP data. DFA was specificallydesigned to be robust against nonstationarity within a time-series The three dependent variables  were evaluatedusing a 2 (Vision: eyes open vs. eyes closed)×2 (Base: open base vs.closed base)×2 (Group: BD vs. control) Repeated Measures ANOVA. Time,Vision, and Base were within-subjects factors while Group served as thebetween-subjects factor. To evaluate possible medication effects on posturalsway performance, participants with bipolar disorder were collapsed into asingle group with medication status as the independent variable. Participantswere divided into three groups: those on antipsychotic medication  were assigned to the “antipsychotic” group(n = 9), those who were on other psychotropic drugs butwere not taking antipsychotic medication were assigned to the “otherpsychotropic” category (n = 3), and those who werenot currently taking medication were included in the “unmedicated”group (n = 4). Repeated measures ANOVAs were then conductedfor all primary dependent variables. In addition, bipolar disorder participantswere coded as “on” or “off” for the following medicationcategories: atypical antipsychotic drug use (ON = 9), SSRIs(ON = 4) and a test of medicated (any psychotropicmedication including antipsychotics) versus unmedicated participants(ON = 12). Separate ANOVAs were conducted for each categoryand for each dependent variable. Finally, chlorpromazine equivalent dosages werecalculated using the method described by Woods 2 (ηP2). Anestimate of effect size was provided by Cohen Results of the major dependent variables are reported with their correspondingeffect sizes in the form of partial etaExemplar plots of COP data from a BD and control participant in the eyes-open andeyes-closed conditions in an open stance are shown in No significant differences for medication status were found for any primarydependent variables, nor were there significant correlations betweenchlorpromazine equivalent dosages and any postural sway variables.Although no participants with current alcohol dependence were included in thestudy, 5 participants with bipolar disorder had previously met criteria forDSM-IV Alcohol Dependence. When these participants were excluded and allanalyses were run including only the remaining 11 who had no history of alcoholdependence, all results involving interactions with and main effects ofdiagnosis reported below were essentially unaltered. All significant resultsusing the entire sample continued to reach significance (p<0.05).2 = 0.23). There was also aninteraction between visual condition and diagnostic group,F = 5.64, p<0.05(ηP2 = 0.16), due to the BD group showingincreased sway compared to the control group in the eyes closed condition. 2 = 0.12), due to the BD groupshowing an increase in sway area in the closed base condition compared tocontrols. A significant within-subjects visual condition x stance interactionwas also apparent  = 7.08, p<0.05(ηP2 = 0.19), in which the eyes closedcondition had a larger effect on the closed base condition relative to the openstance condition. There were also within-subjects main effects of visualcondition, F = 13.50, p = 0.001,ηP2 = 0.31, and stance,F = 17.60, p<0.001,ηP2 = 0.37, where sway areas were smallerduring the eyes open and open stance conditions.The bipolar disorder group had significantly larger sway areas than controls,resulting in a main effect of diagnosis,  = 9.08,p<0.01 (ηPP = 0.16), due to higher α-valuesoverall in the BD group. In addition, there was a vision x diagnostic groupinteraction  = 5.54, p<0.05,ηP = 0.16). A post-hoc analysis of thevision x diagnosis interaction revealed a significant difference betweendiagnostic groups during the eyes-closed conditions (p<0.05) where controlshad lower α-values than the BD participants. DFA results for both groups inthe eyes open and eyes closed conditions can be seen in P = 0.43, where α-values werelower during the open-base conditions in comparison to the closed-baseconditions.The DFA analysis yielded a significant main effect of diagnosis = 5.71, p<0.05,ηP2 = .54) as well as asignificant effect of vision  = 19.23, p<0.001,ηP2 = .39). Post-hocanalysis of the vision x stance interaction revealed that α-values weresignificantly lower (p<0.05) in the eyes open condition when the base wasopen compared to closed; however, α-values were significantly higher(p<0.01) in the eyes closed condition when the base was open compared to whenit was closed. The vision effect showed that α-values were higher when theparticipants' eyes were open.There were no significant interactions or main effects for diagnostic group(p>0.05). A significant within-subjects vision x stance interaction wasobserved,  = 34.88 p<0.001,ηThe primary findings of the present study were that participants with bipolardisorder manifested increased postural sway in comparison to non-psychiatriccontrols and were particularly affected by the loss of visual information. Ourfinding of greater sway across the various stances and vision conditions suggestspoorer postural control in bipolar disorder and is consistent with previous findingsof motor dysfunction in BD A key finding was that the loss of visual information in the eyes closed conditionresulted in increased sway area in the bipolar disorder group, an effect notobserved in controls. This suggests that the BD participants have reduced posturalcontrol when visual information is absent. Interestingly, the narrowing of thestance, which reduces the availability of proprioceptive information, did notcompound the effects of reduced visual information in BD participants. Our resultsalso show that increasing the difficulty of the postural task does not necessarilymagnify differences between controls and participants in the bipolar disorder groupinsofar as there were no significant post-hoc group differences (p>0.05) in themost challenging stance and vision conditions .When dynamical systems analyses were applied to examination of postural sway, groupdifferences became apparent in the medio-lateral but not the anterior-posteriordirection. This finding of less complex dynamics in the BD group compared tocontrols is consistent with the loss of complexity hypothesis in disease anddisorder While the bipolar disorder and control groups had similar responses to manipulationsof proprioceptive input (through changes in stance) overall, differences in swaydynamics between groups were particularly apparent when visual input was removed.Specifically, DFA α-values decreased for controls in the eyes-closed condition,but remained relatively unchanged in the bipolar disorder group. The DFA values forthe BD participants remained high, indicating that their sway dynamics weredominated by slow time-scales of change. The pattern of results observed in thecontrol group, in contrast, indicated that sway dynamics became more complex whenvisual input was removed, consistent with previous studies indicating that visualinformation contributes to low frequency, longer time-scale postural adjustmentsThe fact that the bipolar disorder group maintained high DFA α-values (indicativeof reduced complexity) even when visual input was removed suggests that the BDparticipants were less able to make corrections to their sway pattern when no visualinformation was available. Reduced short time-scale corrections contributes todecreased complexity in postural sway in BD, a finding that is consistent with thepostulation that aging and disease are associated with a loss of complexity due tothe loss of short time-scale components in physiologic systems A consistent finding across the sway area and DFA analyses was that a large declinein postural control occurred in the eyes-closed condition in BD irrespective ofstance. In particular, increased sway area and decreased ability to implementpostural adjustments in the medio-lateral direction in the BD group were apparentcompared to controls when visual input was removed. The convergence of our resultsacross both magnitude and dynamic analysis is important, especially because dynamicanalyses (such as DFA) are often considered a more sensitive assay of postural swayand are able to reflect different properties of postural control that sway areaalone cannot It may be of significance that diagnostic group differences in postural dynamics werefound only in the medio-lateral direction. In general, postural sway in theanterior-posterior direction is primarily generated at the ankle, while posturalcontrol in the medio-lateral direction is the product of hip movements The results of this current study are consistent with previous observations ofcomorbidities between motor dysfunction and mood disorders. For example, inParkinson's Disease, depression is a common feature of the illness One complication in fully understanding the current results is the relativeheterogeneity in the BD participants, as evidenced by the large between-subjectsstandard deviations in sway area. The heterogeneity in the BD group could havearisen as a result of differences in medication regimens. Medication confounds aredifficult to completely eliminate or adequately control for statistically. Gainingaccess to medication naïve patients is also not a completely satisfactoryanswer because such patients are often symptomatic, introducing a confound of acutemood state. Therefore, testing medicated, euthymic patients represents one approachto investigating the underlying mechanisms of bipolar disorder. Testingnever-medicated first-episode (often symptomatic) patients is a complementarystrategy. Each approach presents a different type confound , but nevertheless provides a part of the overall picture of thepathophysiology of BD.The approach we have chosen for this study, i.e., studying euthymic, medicatedpatients, clearly presents difficulties in the interpretation of the present resultsbecause it is difficult to determine what proportion of the effect size arises fromunderlying mechanisms associated with bipolar disorder and what effects were due tomedications. Although the small sample size makes disentangling medication effectsdifficult, an additional, possibly insurmountable obstacle is the number ofdifferent psychotropic medications each participant was on, often with differentpharmacological mechanisms, and their interacting and sometimes opposing effects onpostural control. For example, neuroleptics have been shown to negatively affectsway dynamics In addition, postural sway may have been altered in patients taking lithium. There isevidence that lithium improves motor coordination and balance on the rotarod test ina transgenic mouse model of Huntington's disease In this current experiment, we do not have sufficient statistical power to clearlydelineate how individual medications and course of illness variables such as thenumber of previous mood episodes could have affected postural control. This processis complicated further by the potentially broad range of effects that differentcombinations of medications prescribed to participants could have on motor function.Further longitudinal research with a better controlled, much larger sample isnecessary in order to elucidate the different effects of various medications andtheir combined effects on postural sway in BD. In addition, more comprehensiveinformation regarding the relationship between illness history and postural controlwould be of interest. Overall, however, comparison of participants based oncategories of medication use does provide some evidence that the observed deficitsin motor function cannot be explained as being the effects of the psychotropic drugsalone. It is possible that some interaction between the disorder and medicationsnegatively impacts postural control in BD.Several limitations to the present study suggest caution should be exercised ininterpreting our results. Beyond medication use, several additional sources ofsample variance in the BD group may have influenced the group differences that wereobserved. A number of BD participants in this study had a history of alcohol abuseor dependence, which could contribute to the observed differences between groups.However, the observed pattern of results was unchanged when participants withprevious alcohol dependence were excluded. An additional source of variance isinter-individual differences in illness history. Such course of illness variablescould be particularly relevant given that the number of previous acute mood episodesin bipolar disorder has been associated with the degree of cerebellar atrophy Overall, the evidence presented here is consistent with earlier findings of motorabnormalities in BD


XRCC1) gene, a polymorphism, Arg399Gln (rs25487), has been shown to change neoconservative amino acid and thus result in alternation of DNA repair capacity. Numerous studies have investigated the association between Arg399Gln and breast cancer risk in the American population, but yielding inconsistent results. This study aimed to clarify the role of this polymorphism in susceptibility to breast cancer.In the X-ray repair cross-complementing group 1 , by integrating data from 18 case control studies of 10846 cases and 11723 controls in the American population.Pheterogeneity = 0.003; OR for additive model = 1.07, 95% CI: 1.01–1.14, Pheterogeneity = 0.017). Further sensitivity analysis supported the robust stability of this current result by showing similar ORs before and after removal of a single study.Overall, significant association was observed between the Arg399Gln polymorphism and breast cancer risk under the random-effects model (OR for dominant model = 1.12, 95% CI: 1.02–1.24, XRCC1 Arg399Gln polymorphism may significantly contribute to susceptibility of breast cancer in the American population.This meta-analysis suggests that the  Breast cancer is the most common cancer and a predominate cause of cancer related-death in female population worldwide XRCC1) gene, encoding a scaffolding protein, involved in the repair of single-strand breaks, the most common lesions in cellular DNA XRCC1 active cell would be hypersensitive to DNA damage. In the XRCC1 gene, a functional polymorphism, Arg399Gln (rs25487) has been extensively investigated in many cancers et al. suggested that the variant of Arg399Gln might confer increased risk of breast cancer et al. reported no association of this polymorphism and breast cancer XRCC1 and breast cancer risk in the American population.Base-excision repair (BER), an important DNA repair pathway, is responsible for the repair of base damage resulting from exposure to X-rays, oxygen radicals, and alkylating agents Relevant articles published before April 1st, 2013 were identified through a electronically search in the PubMed, Springer Link, Ovid, EBSCO and ScienceDirect databases using the combination of key words: ‘XRCC1’, ‘polymorphism’, ‘Arg399Gln’, ‘SNP’, ‘variant’, ‘BC’ and ‘breast cancer’. References of retrieved publications were also screened. Disagreements were resolved through discussions between the two authors (Yang Peng and Yong Sun).XRCC1 Arg399Gln and breast cancer risk; (b) patients should be confirmed with histologically breast cancer; (c) studies should provided data about the frequencies of alleles or genotypes. (d) American population is meant that all the inhabitants of America. Meta-analysis, letters, reviews or editorial articles were excluded. If studies shared the same participants, only the one with the largest population or the most complete information was included. If more than one ethnical population were included in one publication, each population was considered separetly. The meta-analysis was conducted according to the guidelines of Preferred Reporting Items for Systemic Reviews and Meta-Analyses statement (PRISMA) http://www.prisma-statement.org).In our meta-analysis, studies were included if they met the all of the following criteria: (a) case-control studies investigated the relationship between The following data from included studies were extracted independently by two authors (Li Zhao and Yang Peng) into a standardized form: the first author's name, year of publication, ethnicity of participants, study design, sample size, pre- and postmenopausal status, genotyping method, allele and genotype frequencies, study population, sample materials of study participants and evidence of Hardy-Weinberg equilibrium (HWE) in controls. In case of conflicting evaluations, disagreements were resolved through discussions between the authors.Two authors independently assessed the quality of included studies according to the 9-star Newcastle-Ottawa Scale. The study quality was assessed by the 9-star Newcastle-Ottawa Scale. A full score is 9 stars, and a score ≥6 stars is considered to be high quality. The quality of case-control studies was assessed as follows: adequate definition of cases, representativeness of cases, selection of controls, definition of control, control for the most important factor or the second important factor, exposure assessment, same method of ascertainment for all subjects, and non-response rate. The score of each individual publications was shown in 2 based Cochran's Q statistic test was employed to test between-study heterogeneity, and heterogeneity was considered significant when P<0.1 for Q statistic. Heterogeneity was quantified by 2I statistic examining the percentage of heterogeneity  For each study, odds ratios (ORs) and their 95% confidence intervals (CIs) as the metrics of effect size were recalculated for additive, dominant [(Gln/Gln+Arg/Gln) versus Arg/Arg] and recessive [Gln/Gln versus (Arg/Gln + Arg/Arg)] genetic models. For additive model, common homozygotes, heterozygotes, and rare homozygotes were assigned as scores of 0, 1, and 2, respectively, and then ORs per unit score were calculated by comparing between cases and controls in logistic regression model. The χP for heterogeneity = 0.003, 0.003 and 0.017 for dominant, recessive and additive models, respectively), and thus the random-effects model was employed. Significant associations were observed between the XRCC1 Arg399Gln and breast cancer risk in both of the dominant and additive models , possibly due to the different sources of controls and ethnicity. Significant association was also seen in this subgroup, with ORs for dominant model and additive model were 1.27 (95% CI = 1.08–1.49) and 1.15 (95% CI = 1.02–1.29), respectively.When stratified by the genotyping method, the significant was effectively removed in TaqMan Real Time PCR and MassARRAY Sequenome subgroup, but no association was found. In the PCR-RFLP subgroup, heterogeneity was seen . No heterogeneity and no significant association were seen in the hospital based subgroup.Subgroup analysis was also performed by sources of controls . The popP for Egger's test >0.10). For the additive model, a borderline significant publication bias was observed (P for Egger's test = 0.04).Given the significant between-study heterogeneity for the Arg399Gln polymorphism, we performed a sensitivity analysis to assess the effects of single study on pooled ORs under a random-effects model . The pooXRCC1. The Arg399Gln variant presented significant association breast cancer risk in the American population. Further sensitivity analysis suggested the stability of the current results, by showing similar ORs before and after sequential removal of single study. This meta-analysis, based on updated published data, has further increased sample size and enlarged the statistical power to reflect the precision effect of the Arg399Gln in breast cancer in the American population.This meta-analysis incorporated 18 studies of 10846 breast cancer cases and 11723 controls concerning the Arg399Gln in XRCC1 plays an important role in the BER pathway, which has been thought of as the predominant DNA-damage repair pathway for the processing of small base lesions derived from oxidation and alkylation damage XRCC1 in maintaining genomic stability has been raised by high frequency of chromosome deletions or aberrations in the gene mutant cells, and thus the XRCC1 gene has been posed as a candidate gene for many cancer susceptibility. In the coding region of XRCC1, the nonsynonymous polymorphism, Arg399Gln, has caught much attention in breast cancer risk for years. This polymorphism is located in the critical COOH-terminal side of PARP-binding BRCT-domain XRCC1 Arg399Gln polymorphism is significant associated with of breast cancer in the American population. Intriguingly, the significant association was presented in the dominant and additive models, which is inconsistent with the most recent meta-analysis et al., the AA genotype frequency in controls was 194; however, in the meta-analysis by Huang Y et al. and Wu K et al., it changed to 280, which would influence the accuracy of the pooled analysis. Additionally, Caucasian and African-American assessed in the previous meta-analysis were distinct with our meta-analysis, possibly resulting in the inconsistent result with our meta-analysis.XRCC1 with breast cancer has been investigated in many other countries. In China, Liu L et al. reported XRCC1 -77T>C may be a genetic determinant for developing breast cancer et al. find that XRCC1 T-77C could be genetic determinant for prognosis of advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy XRCC1 Arg399Gln polymorphism maybe also associate with breast cancer.The association of Nevertheless, significant between-study heterogeneity was seen in this meta-analysis. To explore the source of heterogeneity, we performed subgroup analysis. After stratified by premenopausal or postmenopausal status, heterogeneity was significant removed, indicating that the premenopausal or postmenopausal status may be one source of heterogeneity. According to ethnicity, we found that for recessive and additive models, heterogeneity was effectively removed in Africans and Caucasians, whereas for dominant model, it retained in Africans and Caucasians, but in the mixed population, no evidence of heterogeneity was shown, suggesting ethnical population may also partly explained the heterogeneity of this meta-analysis. With regard to the control source, heterogeneity was removed in hospital-based subgroup, but was detected in population-based subgroup. Furthermore, the results of PCR-RFLP subgroup analysis were similar to population based subgroup analysis. Heterogeneity was also partly explained by population based and genotpying method of this meta-analysis. Moreover, all the included studies showed high quality (≥6 stars) by the 9-star Newcastle-Ottawa Scale, and no publications bias was observed in dominant and recessive models.Several limitations in this meta-analysis should be figured out. First, in the subgroup analysis by ethnicity and premenopausal/postmenopausal status, the sample size was relatively small and the statistical power might be insufficient. Second, potential sources of heterogeneity in this meta-analysis could include other factors, such as family history of breast cancer, staging of breast cancer, history of begin breast disease. However, due to the limited data, we failed to further explore these factors in the current meta-analysis. Finally, multiple epidemiological studies have demonstrated gene-gene or gene-enviroment interactions may play more important role in cancer development as compared with genetic factors XRCC1 Arg399Gln polymorphism was significantly associated with risk of breast cancer in the American population. Nevertheless, in the future, well-designed studies with large sample sizes will be warranted in diverse populations.In conclusion, this meta-analysis provided evidence that the Checklist S1The PRISMA 2009 Checklist.(DOC)Click here for additional data file.Figure S1Forest plot of the association between the XRCC1 Arg399Gln and breast cancer risk for the recessive model.(TIF)Click here for additional data file.Figure S2Forest plot of the association between the XRCC1 Arg399Gln and breast cancer risk of menopausal subgroup for the dominant model.(TIF)Click here for additional data file.Figure S3Forest plot of the association between the XRCC1 Arg399Gln and breast cancer risk of menopausal subgroup for the recessive model.(TIF)Click here for additional data file.Figure S4Forest plot of the association between the XRCC1 Arg399Gln and breast cancer risk of menopausal subgroup for the additive model.(TIF)Click here for additional data file.Figure S5Sensitivity analysis of the association between the XRCC1 Arg399Gln and breast cancer risk the recessive model.(TIF)Click here for additional data file.Figure S6Funnel plot of the association between the XRCC1 Arg399Gln and breast cancer risk for the recessive model.(TIF)Click here for additional data file.Table S1Quality assessment of case–control studies included in this meta-analysis.(DOC)Click here for additional data file.Table S2Data of premenopausal or postmenopausal studies.(DOC)Click here for additional data file.


OR) and 95% confidence interval (95% CI) were calculated with random-effect model or fixed-effect model based on the heterogeneity analysis. The quality of included studies was evaluated by using the Newcastle-Ottawa Scale. The sensitivity analysis was used to confirm the reliability and stability of the meta-analysis. In total, 20 case-control studies with 9122 cases of T2DM and 8017 controls were included. Among these case-control studies, we selected 13 ones on rs7903146 C/T, 5 ones on rs12255372 G/T, 8 ones on rs290487 T/C. The results indicated that rs7903146C/T polymorphism was significantly associated with T2DM . There was no evidence that rs12255372G/T and rs290487T/C polymorphisms increased T2DM risk . Subgroup analysis of different regions proved the relationship between rs7903146C/T polymorphism and T2DM risk in both the northern and the southern China. The association of rs290487 with T2DM was affected by body mass index, whereas the association of rs7903146 and rs290487 with T2DM was influenced neither by age nor by sex. In conclusion, this study indicated that the rs7903146C/T polymorphism of the TCF7L2 gene had a significant effect on T2DM risk in Chinese Han population, with rs12255372G/T and rs290487T/C polymorphisms showing no significant effect.In recent years, it has been widely accepted that transcription factor 7-like 2 (TCF7L2) is associated with type 2 diabetes mellitus (T2DM) in multiple ethnic groups, especially its single nucleotide polymorphisms of rs7903146C/T, rs12255372G/T and rs290487T/C. However, the results previously obtained in Chinese Han population are often inconsistent. For clearing this issue, herein we performed meta-analysis based on the reports that can be found to assess the association. In the meta-analysis, Odds ratio ( One of the most challenging health problems of the twenty-oneth century is type 2 diabetes mellitus (T2DM). It represents a significant disease burden on human beings, both in developed and developing countries T2DM is a complex metabolic disease that results from the combination of genetic and environmental factors In this work, we conducted a meta-analysis with large samples based on the representative single nucleotide polymorphisms in Chinese Han population, which have already been much studied. The meta-analysis method using all available studies has proved to be more powerful and can lead to more reliable conclusion in comparison with a single study. Therefore, we employed this method to evaluate the association between TCF7L2 polymorphisms and the T2DM risk in Chinese Han population.Our study followed the statement of PRISMA for reporting systematic review and meta-analysis In this meta-analysis, we searched literature from the following databanks: China National Knowledge Infrastructure (CNKI), PubMed, Embase, Elsevier, Springer Link, Cochrane Library, and ISI Web of Science. The searching languages included English and Chinese. The employed key words and subject terms were TCF7L2, transcription factor 7-like 2, rs7903146, rs12255372, rs11196218, rs11196205, rs7901695, rs290487, gene polymorphism, diabetes mellitus, type 2, type 2 diabetes mellitus, T2DM, and T2D. Furthermore, the reference lists of thus-obtained eligible studies and relevant review papers were identified by a manual search on this topic. The last research was updated until August 15, 2012.OR) and corresponding 95% confidence interval (CI). The following studies were excluded: (1) those contained duplicate data; (2) those reported in the form of abstract, comment, and review; (3) those except for that using the largest samples, if the identical group published more than one articles based on the same data series.The primary studies included in our meta-analysis should meet the following criteria: (1) the association between TCF7L2 polymorphisms  and T2DM risk in Chinese Han population should be clearly evaluated; (2) the studies must be of case-control study; (3) the papers should clearly describe the diagnoses of T2DM and the sources of cases and controls; (4) the studies should provide original data and sufficient information to estimate odds ratio  For quality control, data were extracted from the studies independently by two of our authors. If the information of genotype distribution was inadequate, we tried to contact the authors of the related paper. The following information was extracted from each article: the last name of the first author, publishing year, region, numbers of cases and controls, numbers of genotypes for cases and controls, and Hardy-Weinberg equilibrium (HWE) in each control group. Any disagreement between our two authors was resolved by consulting the third.This article was on a meta-analysis. We got the data from previous studies. All the data were analyzed anonymously. We confirmed that all the data did not involve competing interest.OR) and 95% confidence interval (CI) were used to assess the strength of the association between polymorphisms of TCF7L2 and T2DM risk, which were calculated by fixed-effect model or a random effect model chosen based on the heterogeneity test 2χ-based Q-test reported a P value of more than 0.10, we used the fixed-effect model 2I test. The 2I statistic was documented for the percentage of the observed study variability due to heterogeneity rather than chance.  Z-test. When the Z-test reported a P < 0.05, there was statistical significance for the association.In this study, we performed both overall and subgroup meta-analysis. In both kinds of the meta-analysis, pooled odds ratios (P<0.05) between the cases and the controls were assigned to the incomparability subgroup of age, while those with P>0.05 were assigned to comparability subgroup. The subgroup analysis was also performed based on Hardy-Weinberg equilibrium (HWE). As HWE is the principal law of the population genetic studies, we calculated p value of HWE for the control group of each study based on the Pearson chi-square. If the P>0.05, the focus would conform to HWE and the samples of control would be representative.The subgroup meta-analysis was employed to reveal the effect of different regions on the overall estimation of the association. The whole region of China was divided into two parts with the Yangtze River as the boundary A sensitivity analysis was carried out to assess the stability of the meta-analysis results. That is to say, by omitting one case–control study at a time, the pooled OR for the remaining studies was computed. If the pooled OR was not changed by the single study, this result would be stability.P-values were two-tailed. The Review Manager 5.0 software  was used to carry out the meta-analysis.In our literature, funnel plots were used to evaluate publication bias. All OR = 1.73, 95% CI = 1.39–2.16, P<0.00001; heterogeneity test χ2 = 30.32, P = 0.003, I2 = 60%).There was significant heterogeneity among the studies of rs7903146C/T in the overall meta-analysis. Therefore, the random effect model was employed to assess the association between rs7903146C/T polymorphism and T2DM risk. The evaluation result indicated that rs7903146C/T polymorphism was associated with T2DM risk . The subgroup meta-analysis of different regions also confirmed that there was association between rs7903146C/T polymorphism and T2DM risk in both the northern and the southern China .The subgroup meta-analysis of the studies which conformed with HWE in the control groups showed that there was association between rs7903146C/T polymorphism and T2DM risk . The effect of the BMI on the association was not examined since there was only one study based on the comparability of BMI.By the subgroup meta-analysis of the studies based on the confounder factors like age and sex, it was illustrated that the association between rs7903146C/T polymorphism and T2DM was not affected by these two factors .Significant heterogeneity was found among the studies of rs12255372G/T in the overall meta-analysis. Thus, the random effect model was used to evaluate the association between rs12255372G/T polymorphism and T2DM risk. The evaluation result indicated that rs12255372G/T polymorphism was not associated with T2DM risk . The subgroup meta-analysis also demonstrated that there was no association between 12255372G/T polymorphism and T2DM risk in the southern China . We did not evaluate such association for the subgroup of the northern China since there were not sufficient data.The subgroup meta-analysis of the studies which conformed with HWE in the control groups showed that there was no association between 12255372G/T polymorphism and T2DM risk (as shown in 2I = 80%) of sex comparability subgroup and insufficient studies with regard to the age and BMI comparability.The subgroups analysis of the studies based on age, sex, and BMI was not carried out due to the extreme heterogeneity .Significant heterogeneity was also observed among the studies of rs290487T/C in the overall meta-analysis. Hence the random effect model was chosen to illustrate the association between rs290487T/C polymorphism and T2DM risk. The result confirmed that rs290487C/T polymorphism was not associated with T2DM risk . Both the subgroup meta-analysis of the southern or the northern China indicated that there was no significant association between rs290487T/C polymorphism and T2DM risk .Based on the subgroup analyses with HWE in the control groups, we did not find any association between rs290487T/C polymorphism and T2DM risk . The subgroup analysis of age incomparability was not conducted because of insufficiency studies.The subgroup meta-analysis of the studies based on age illustrated that there was no significant association between rs290487T/C polymorphism and T2DM risk . On the other hand, the subgroup meta-analysis based on BMI showed that the association was affected by this cofounder factor .The subgroup meta-analysis of the studies based on sex illustrated that this association was not affected by sex . For this reason, we evaluated the association between rs7903146C/T polymorphism and T2DM risk by the fixed-effect model, and the interaction was confirmed . For the sensitivity analysis of rs12255372, if omitting the study of Fan OR = 1.26, 95%CI = 0.81–1.95, P = 0.30; heterogeneity test χ2 = 0.37, P = 0.95, 2I = 0%).The sensitivity analysis of the studies on rs7903146 showed no heterogeneity, if omitting the studies by Chang The shape of the funnel plots on the studies of rs7903146C/T polymorphism was symmetrical, suggesting that there was no evidence of publication bias for rs7903146C/T polymorphism  and T2DM risk in Chinese Han populations. The protocol of this meta-analysis has been well designed primitively by using explicit methods and criteria for study selection, data extraction, and data analysis. Perfect searching strategy based on computer-assisted search together with manual search has been applied to include eligible studies as many as possible. Finally, the quality of included studies in our meta-analysis is relatively satisfactory. Since the number of studies and subjects included in our meta-analysis were relatively small, however, the funnel plots could not be made in the two SNPs (rs12255372G/T and rs290487T/C), which could not avoid possible publication bias in our analysis.. We expect that the case-control studies with large and family-based samples had better be carried out in the future to provide sufficient data for better meta-analysis, considering low frequency of TCF7L2 gene, a variety of confounders, and two substructures in Chinese Han.In conclusion, this meta-analysis indicated that, in Chinese Han population, the rs7903146C/T polymorphism of TCF7L2 gene was associated with T2DM risk, while the polymorphisms of rs12255372G/T and rs290487T/C were notTable S1The PRISMA checklist for this meta-analysis.(DOC)Click here for additional data file.