Epidemiological studies have suggested that variants on adiponectin (ADIPOQ) and its receptor ADIPOR1 (adiponectin receptor 1) are associated with colorectal cancer (CRC) risk; however, the results were inconclusive. The aim of the study was to evaluate the associations between the variants on ADIPOQ and ADIPOR1 and the CRC risk with a hospital-based case-control study in the Chinese population along with meta-analysis of available epidemiological studies.With a hospital-based case-control study of 341 cases and 727 controls, the associations between the common variants on ADIPOQ  and ADIPOR1 (rs1342387 and rs12733285) and CRC susceptibility were evaluated. Meta-analysis of the published epidemiological studies was performed to investigate the associations between the variants and CRC risk.2 = 50.4%). The case-control study found no significant association for variants rs266729, rs822395, rs2241766, and rs1501299 on ADIPOQ or variant rs12733285 on ADIPOR1 and CRC susceptibility, which were consistent with results from the meta-analysis studies.For the population study, we found that variant rs1342387 of ADIPOR1 was associated with a reduced risk for CRC . The meta-analysis also suggested a significant association for rs1342387 and CRC risk; the pooled OR was 0.79 (95% CI = 0.66-0.95) for the CT/TT carriers compared to CC homozygotes under the random-effects model  contains supplementary material, which is available to authorized users. Along with the increasing incidence of the obesity and the mortality rate of the obesity related diseases worldwide, hyperinsulinemia and insulin resistance that are likely to confer an increased risk of colorectal cancer (CRC) have drawn more attention . Epidemietc., and they mediate the anticancer activities of adiponectin in the cells. ADIPOQ gene deficient mice showed an increased incidence of colon polyps in relative to wild-type mice when they were fed with a high-fat diet  . The pre2 statistic. Heterogeneity between the studies was considered significant when P < 0.1 for the Q-test or the I2 value was more than 25%. If significant heterogeneity between studies was found, the overall pooled estimate under the random-effects model rather than the fixed-effects model was acceptable. Publication bias was graphically represented by funnel plotting and was further assessed by Egger’s linear regression test [http://www.r-project.org/).For the meta-analysis, the pooled OR and its 95% CI for the dominant genetic effect model of the selected variants were calculated using the standard inverse variance weighting method for the fixed-effects model and the DerSimonian-Laird method for the random-effects model. Heterogeneity between studies was assessed using the Cochrane’s Q-test together with the Iion test . SensitiThe characteristics of the participants recruited are shown in Table ADIPOQ, which may influence the circulating adiponectin levels, there was no significant association with CRC risk under any genetic model (Table ADIPOQ or rs12733285 on ADIPOR1) was significantly associated with CRC risk  for the CT and TT carriers in relative to CC carriers. No significant publication bias was found . Thus, the results suggested that rs1342387 may contribute to the susceptibility of CRC, which were consistent with the results of our population study.The four included reports, with five individual studies that recruited a total of 1,871 cases and 2,597 controls, have evaluated the association between variant rs1342387 and CRC risk . From the literature search, we identified six studies with seven subgroup studies that recruited a total of 3,635 cases and 4,411 controls  under the random-effects model. No significant publication bias was detected for the meta-analysis studies. The data indicated that rs266729 may be not a susceptibility factor for colorectal cancer.rs266729 was firstly identified as a potential susceptibility locus on et al. [2 = 0%) for the TG/GG carriers compared to TT carriers. For rs1501299, sensitivity analysis indicated that the study conducted by Tisilidiset al. [2 = 0%) for TG/GG carriers compared to TT carriers after the study was excluded in the meta-analysis study. No significant publication bias was found, as determined by Egger’s test for all the meta-analysis studies . The meta-analysis study found no significant association between the variant and CRC risk; however, the sensitivity study suggested that the results may be affected by the heterogeneity between the studies. rs1501299 is located on intron 2 (+276 G > T) of ADIPOQ and the meta-analysis conducted by Xu et al. found a decreased CRC risk for GT and TT carriers compared to GG carriers; however, only four studies were included [et al. [ADIPOQ, and rs12733285 is located on intron 1 of ADIPOR1. Neither variant showed a significant association with CRC risk in our population study or in the meta-analysis studies.For the other four variants, we found no significant association with CRC risk in our hospital based case-control population study, which was consistent with the results of the meta-analysis studies. For variant rs2241766, which is located on exon 2 of included . For theWe acknowledged that there were several limitations for the current study. Firstly, the investigation was a hospital based case-control study, which is more prone to selection bias of the participants. The age of the control subjects was slightly younger than that for the CRC cases, and the CRC risk for the controls was difficult to determine. Secondly, the relatively small sample size may lead to a lower statistical power to detect the association between rs266729 and other variants with CRC risk. Lastly, the underlying mechanisms for the association between rs1342387 and CRC risk need to be elucidated.ADIPOR1 may contribute to CRC susceptibility. Results from our population study and meta-analysis suggest that variants rs266729, rs822395, rs2241766, and rs1501299 of ADIPOQ and variant rs12733285 of ADIPOR1 may not contribute to CRC susceptibility. However, more investigations with larger sample sizes are warranted to validate these results and the underlying mechanisms are also need to be elucidated.In conclusion, variant rs1342387 of


LAPTM4B is a newly cloned gene that shows an active role in many solid tumors progression in substantial researches, mainly through the autophage function. Accumulated studies have been conducted to determine the association of LAPTM4B polymorphism with cancer risk. While the results are inconsistent, we conducted the meta-analysis to determine the strength of the relationship. Results showed that allele*2 carriers exhibited a significantly increased risk of cancer development with comparison to allele*1 homozygote . We also observed a significant association between *2/2 homozygote and cancer risk with comparison to allele*1 containing genotypes . Allele*2 is a risk factor for cancer risk . Stratified analysis by tumor type exhibits the significant association of this genetic variants with various cancers. In conclusion, LAPTM4B polymorphism is associated with cancer risk and allele*2 is a risk factor.The online version of this article (doi:10.1186/s40064-015-0941-7) contains supplementary material, which is available to authorized users. Lysosomes are organelles that contain hydrolytic enzymes such as proteases, nucleases and lipases. The stability of lysosomal membrane and the normality of lysosomal function are essential in cellular biology. Lysosomal-membrane permeabilization (LMP) can pose a threat to cellular homeostasis through release of lysosomal contents, such as lysosomal cathepsins B or D, and is a recognized trigger of cell death  is a recently discovered gene mapped to chromosome 8q22.1 with 7 exons and 6 introns spanning at least 50 kb .Begger’s plot funnel and Egger’s test were performed to examine the underlying publication bias. The symmetrical plot funnel and p value >0.05 for Egger’s test indicated no publication bias in this meta-analysis Figure .Figure 3Due to insufficient angiogenesis, tumors frequently experience elevated metabolic stress from nutrient and oxygen deprivation  binding domain at C-terminal and specific src-homology 3(SH3) binding domain at N-terminal. The functional domain in C-terminal has a lysosome localization motif, sharing the same domain with the markers of endosomes and lysosomes )”. Citation indexes were performed and the reference list was searched to identify potential relevant studies. The last search update was Jun 29, 2014.Studies involved in the meta-analysis should meet the following inclusion criteria: (i) a case–control study; (ii) frequency of genotype or allele is available; (iii) P value of Hardy-Weinberg equilibrium for the distribution of genotypes in control group should be no less than 0.05.Articles will be excluded for: (1) no available data to calculate OR or no original data to estimate the P value of Hardy-Weinberg equilibrium; (2) duplicate publication; (3) meeting records or articles written neither in English nor in Chinese.Two authors worked independently to extract information carefully. Any disagreement would be discussed until a consensus was reached between two authors. Otherwise, another author would check up the controversial information and a final conclusion would be drawn from the vote results. The information collected from each study contained: the surname of first author, the publication year, country of origin, ethnic group, type of tumor, frequency of genotypes and alleles in cases and controls.The strength of the association of LAPTM4B polymorphism and cancer risk is measured by odd ratios (ORs) with 95% confidence intervals (CIs). The statistical significance of the pooled ORs is determined by Z-test. We estimated the cancer risk related to allele*2, compared to allele*1. For genotypes, we estimated the OR associated with genotype *1/2, *2/2 and allele*2 containing genotypes (*1/2 + *2/2), compared with *1/1 homozygote, respectively. Stratified analysis was performed according to the type of tumor.Hardy-Weinberg equilibrium (HWE) was tested by chi-square goodness of fit and a P value no less than 0.05 indicates that the study complies with Hardy-Weinberg Law. The degree of heterogeneity among studies was investigated by Q-statistic. A P value >0.05 indicated a lack of heterogeneity among studies and we chose the fixed effect model (the Mantel-Haenszel method). Otherwise, we selected a random effect model (DerSimonian–Laird method). A funnel plot was used to decide the presence of publication bias, in which the standard error of log (OR) of each study was plotted against its log (OR) and an asymmetric plot suggested the existence of publication bias. Egger’s test was then performed to verify the presence and determine the degree of asymmetry. P < 0.05 was considered to indicate the statistically significant publication bias. A sensitivity analysis was carried out to identify the potential outliers. P values were all based on two-way tests. The meta-analysis was performed in STATA version 11.0.


However, the data remain conflicting. The aim of the present meta-analysis was to estimate the overall association between risk of CAD and eNOS 4b/a polymorphism. Case-control, cohort or cross-sectional studies evaluating the association between eNOS 4b/a polymorphism and CAD susceptibility were systematically identified in PubMed up to 31 October 2013. Pooled odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated to assess the association in overall and subgroup analyses. A total of 10,617 cases and 8302 controls from 37 studies were included in the study. The results of overall analysis revealed significant positive associations between CAD risk and eNOS 4b/a polymorphism in homozygote comparisons , heterozygote comparisons  and dominant models . In subgroup analyses, similar associations were identified in African individuals, as determined using population-based source subgroups and noted in small-and-moderate sample size subgroups (case sample size or control sample size <500). The current meta-analysis revealed that eNOS 4b/a polymorphisms could be a risk factor for developing CAD, particularly in African populations and population-based subgroups.A variety of studies have suggested that the 4b/a polymorphism in the endothelial nitric oxide synthase ( CAD il-arginine by the action of nitric oxide synthase (NOS). There are at least three isoenzymes of NOS: inducible NOS, neuronal NOS, and endothelial NOS (eNOS) [eNOS gene is located on chromosome 7q35–q36 and is sized 21 kilobases (kb) [eNOS gene affected NO availability and were associated with CAD morbidity. One of the most clinically relevant eNOS variants forms 27-basepair (bp) tandem repeats in intron 4 (4b/a). The eNOS 4b allele contains five repeats of the 27 bp sequence, whereas eNOS 4a, which is the rare allele, carries a deletion of one of the first three of these repeats [Nitric oxide (NO) is an important atheroprotective mediator that helps mediate endothelium-dependent vasodilatation. Abnormalities in NO generation could play an important role in the pathophysiology of CAD . NO is sS (eNOS) . The eNOses (kb) . A numbe repeats .eNOS 4b/a gene polymorphisms and CAD remains controversial, and the results of two previous meta-analyses were inconsistent [et al. performed a meta-analysis of 16 studies and found an increased risk of ischemic heart disease (IHD) in individuals carrying the homozygous a allele compared with the b allele [eNOS 4b/a did not significantly increase the risk of developing CAD [eNOS 4b/a polymorphisms and the CAD risk have been published since 2010. Therefore, we performed a meta-analysis using a more complete database to clarify the association between eNOS 4b/a polymorphisms and CAD risk.The association between nsistent ,11. In 2b allele . However2.2.1.4b/a polymorphism included 10,617 CAD cases and 8302 controls. The study characteristics are summarized in A total of 373 papers were initially identified during the literature search and from other sources; 37 of these met the inclusion criteria for this analysis ,12–47. A2.2.eNOS 4b/a polymorphisms and CAD risk are summarized in eNOS 4b/a polymorphism were identified in the homozygote comparison , the heterozygote comparison  and the dominant model .The relationship between p = 0.070 for the homozygote comparison; OR = 1.16, 95% CI = 1.00–1.35, p < 0.001 for the heterozygote comparison; and OR = 1.21, 95% CI = 1.05–1.40, p < 0.001 for the dominant model). There was no significantly increased CAD risk in the hospital-based subgroup   .p = 0.080) and the dominant model . Non-Asians were then further stratified into Caucasians, Africans, and others. The populations of an American study and a Brazilian study were both composed of two ethnicities: Caucasians and Africans [p = 0.821; heterozygote comparison OR = 1.46, 95% CI = 1.16–1.83, p = 0.353; and the dominant model OR = 1.58, 95% CI = 1.27–1.96, p = 0.370). Interestingly, significant associations were also found in Asian  and “other”  populations during the homozygote comparison. In contrast, no statistically significant associations were identified in Caucasian populations   .eNOS 4b/a polymorphisms and CAD risk were observed in the small-and-moderate case sample subgroup  but not in the large case sample subgroup. The data were then stratified into large control  and small-and-moderate control sample  subgroups. Similar to the data from the case sample size analyses, significant associations were observed in the small-and-moderate control sample subgroup , but not the large case sample subgroup.The data were then also stratified according to case sample size into large  and small-and-moderate case sample  subgroups. Significant associations between eNOS 4b/a polymorphisms and CAD risk with the homozygote comparison , heterozygote comparison , and dominant model  in patients with MI.Finally, a subgroup analysis for MI was performed. There were significant associations between 2.3.ab + bb vs. aa, pheterogeneity = 0.213, I2 = 15.4%), while the results of heterogeneity tests were significant in the other three genetic models . The random-effects models were used in all the four genetic models. Meta-regression analyses were then performed to evaluate the extent to which different variables explained the heterogeneity. The results revealed that the heterogeneity could be explained by case sample size (p = 0.015) and total sample size (p = 0.015) in the homozygote comparison. However, population ethnicity, year of publication, source of control population, total sample size, and outcome were not statistically correlated with heterogeneity (p > 0.05).There was minor heterogeneity among studies in the recessive model , and the dominant model . The shape of the funnel plot for the homozygote comparison appeared to be approximately asymmetrical, which was confirmed by the test results . However, adjusting the model by the trim and fill method did not influence the conclusions   .2.5.eNOS 4b/a polymorphisms were significantly associated with CAD in three genetic models . These data suggest that carriers of the a allele of the eNOS 4b/a gene might be predisposed to CAD. Heterogeneity was observed in these three models; however, subsequent meta-regression analyses revealed that case and total sample size could explain the heterogeneity. Subgroup analysis based on source of the control population revealed that population-based subgroups with the aa or ab genotypes had a significantly increased risk of CAD. In stratified analyses according to ethnicity, significantly increased risk was detected in the African subgroup with the aa or ab genotypes and the Asian subgroup with the aa genotype. Positive associations were also identified in studies whose case or control sample size was <500 with the aa or ab genotypes. Similarly, significant associations were identified in studies with the aa or ab genotypes in a subgroup analysis according to MI.The meta-analysis revealed that a allele group (31.2 ± 2.00 μmol/L) were significantly lower than in the b allele group (35.5 ± 0.93 μmol/L) [a allele were also identified in a study by Rittig et al. in a German population [eNOS 4b/a gene polymorphisms could contribute to CAD risk by decreasing NO production, which subsequently affects the development of CAD. However, because this variant is located in the intronic region, it is possible that it is in linkage disequilibrium with other functional variants in regulatory regions of the NOS gene. In 2002, Wang et al. demonstrated that the eNOS 4a allele coordinated with the T-786C variant in the promoter region to regulate the transcriptional efficiency of eNOS in a haplotype-specific fashion [et al. reported that the eNOS 4b/a polymorphism affected the bioavailability and activity of NO via linkage disequilibrium with T-786C and G894T variants [eNOS 4a allele had a higher CAD risk than subjects carrying the 4b allele.In 1998, a Japanese study including 413 subjects reported that the plasma levels of mono-nitrogen oxides in the  μmol/L) . Reducedpulation . Prevailpulation ,51. Ther fashion . In 2013variants . Consist4a allele might be a risk factor for CAD among population-based but not hospital-based subgroups. One explanation for this is that there were differences in the frequency of exposure to risk factors between hospital- and population-based studies. The use of hospital-based population might limit the general applicability of the data. Furthermore, the sample size and number of studies in the hospital-based group might not be sufficient to evaluate potential associations.Our results also suggested that the 4a carriers was identified among African and Asian populations but not Caucasians. The results could be explained by varying susceptibility of different ethnicities to the eNOS 4b/a polymorphism among different ethnicities. Environmental characteristics might also contribute to this discrepancy.In the subgroup analysis according to ethnicity, an increased risk in eNOS 4b/a and CAD risk have been performed. In 2004, one study reported an association between eNOS 4a/a and ischemic heart disease compared with eNOS 4b/b [eNOS genetic variant and CAD risk [et al. and in the current meta-analysis differed. Second, we performed overall analyses in four genetic models; in contrast Li et al. did not perform homozygote comparison and heterozygote comparisons. We also performed subgroup analysis based on ethnicity, the source of the control population, and case sample size to identify all possible associations between 4b/a polymorphisms and CAD; these factors were not investigated previously.Two previous meta-analyses assessing NOS 4b/b . AlthougCAD risk ; therefoCAD risk –56. We aThe present study has some limitations. First, heterogeneity was detected in three genetic models, suggesting that results should be interpreted with caution. Second, most of the included studies were case-control studies, where the cases were survivors of cardiovascular events; those who did not survive were not enrolled. Finally, the sample size in the studies was inadequate. The insufficient sample size might increase the probability of false positives or false negatives.3.3.1.We systematically searched PubMed using the following medical subject headings (MeSH) or search terms:  and (“polymorphism*” OR “variation”) and . The search covered all English language publications within a range of published years from 1996 to 2013 (the last search was performed on 31 October 2013). The bibliographies of previous meta-analyses and published reviews were also checked for additional relevant publications.3.2.eNOS intron 4b/a variable number of tandem repeats (VNTR) polymorphisms and CAD susceptibility; (3) studies that provided complete data regarding genotype number and allele frequencies; (4) studies in which CAD was diagnosed based on coronary angiography as well as clinical criteria with clearly reported details; (5) studies that also included controls demonstrated to lack CAD either by coronary arteriography or by clinical criteria; and (6) studies that were published in English. The exclusion criteria were as follows: (1) insufficient data regarding genotypes and allele frequencies; (2) unconfirmed diagnosis of CAD; (3) the genotype distribution of the control population did not conform to HWE; and (4) overlapping publications.The inclusion criteria for studies were as follows: (1) independent case-control, cohort or cross-sectional studies; (2) studies that evaluated the association between 3.3.Two researchers (Y.Y. and K.D.) extracted information including the first author, year of publication, country, ethnicity of the study population, source of controls, genotype number in cases and controls, HWE in controls and study outcome. Data were extracted separately and compared to reach a consensus. Different ethnicities were categorized as Asians and non-Asians . Different ethnic descents in one study were considered to be independent studies when subanalyses based on ethnicity were performed.3.4.eNOS 4b/a gene polymorphisms and CAD was compared using the odds ratio (OR) corresponding to a 95% confidence interval (95% CI). We used four different genetic models in our analysis: homozygote comparison (aa vs. bb), heterozygote comparison (ab vs. bb), dominant (aa + ab vs. bb), and recessive models (aa vs. ab + bb).The association between p values for the Q statistic and I2 values. Significance was set at the p < 0.1 level; p < 0.1 for the Q test indicated there was heterogeneity across the studies and p > 0.1 for the Q test indicated a lack of heterogeneity among studies. The random-effects model was used to estimate the pooled OR according to the DerSimonian and Laird method [I2 was calculated to describe the percentage of variation caused by the heterogeneity: 0%–25%, no heterogeneity; 25%–50%, moderate heterogeneity; 50%–75%, large heterogeneity; and 75%–100%, extreme heterogeneity).Heterogeneity between studies was assessed using d method . I2 was p < 0.05, and the trim and fill method was performed when bias was detected. STATA 12.0 software was used to perform all statistical analyses .To determine the source of heterogeneity across studies, logistic meta-regression analyses were performed. Publication year, population ethnicity, source of the control group, outcome, total sample size, case sample size, control sample size, and the ratio of case size to control size were examined to evaluate the extent to which different variables explained any observed heterogeneity. Stratified analyses were also performed for ethnicity, source of controls, and case sample size. Sensitivity analyses were conducted by removing each study individually and consecutively from the combined data set. Re-analysis of the remaining studies, allowed the robustness of the main findings to be tested. In addition, a funnel plot was used to estimate the potential publication bias; Begg’s and Egger’s tests were then used to examine funnel plot asymmetry with significance set at 4.eNOS 4b/a polymorphisms could increase the risk of CAD, particularly in African populations and among the population-based studies. Further studies with larger sample sizes should be performed to confirm these findings.In conclusion, the results of the current meta-analysis suggested that


GSTM1, GSTT1, and GSTP1 polymorphisms and the risk of schizophrenia. Twelve case-control studies were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Our meta-analysis results revealed that GSTM1, GSTT1, and GSTP1 polymorphisms were not related to risk of schizophrenia (p > 0.05 in each model). Further analyses based on ethnicity, GSTM polymorphism showed weak association with schizophrenia in East Asian population . In conclusion, our meta-analysis indicated the GSTM1 polymorphism may be the only genetic risk factor for schizophrenia in East Asian population. However, more meta-analysis with a larger sample size were needed to provide more precise evidence.The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the  Schizophrenia is a mental disorder that is characterized by abnormal social behavior and altered perception of reality. Several studies suggested that genetic background and environmental factors play an important role in the development of schizophrenia. Recently, there has also been increasing interest in the role of free oxidative stress in the pathogenesis of schizophrenia. Oxidative damage and neuronal inflammation can lead to the onset of schizophrenia ,2,3,4,5.S-transferases (GSTs) are a family of eukaryotic and prokaryotic phase II metabolic isozymes. GSTs are one of the key enzymes that regulate the conversion of toxic compounds to hydrophilic metabolites for the purpose of detoxification [Glutathione fication ,7. In adfication ,8,9. GSTfication . It suggGSTs genes described as polymorphic in humans are glutathione S-transferase Mu1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) [GSTM1 gene is located at 1p13.3, and the most common polymorphism in GSTM1 is a deletion of the whole GSTM1 gene with a lack of enzyme activity. The GSTT1 gene is located at 22q11.2, and a homozygous deletion in GSTT1 has also been reported. The GSTP1 gene is located at 11q13, and the functional polymorphism at codon 105 in exon 5 of GSTP1 has been found [GSTM1, GSTT1, and GSTP1 have been investigated with various diseases including schizophrenia, hypertension, and capacity for oxidation and detoxification [GSTM1 or GSTT1 deletion polymorphisms were contributed to the loss of GST enzyme activities, respectively. So, combination in these GSTM1 and GSTT1 polymorphisms have been also investigated in order to find relationship with various diseases.Human cytosolic GSTs belong to the alpha, zeta, theta, mu, pi, sigma, kappa, and omega classes and the main  (GSTP1) ,12,13,14fication ,16. PrevGSTs gene and risk of schizophrenia in diverse populations. However, these results from the published studies remain conflicting rather than conclusive.Up to now, a number of studies have evaluated the association between polymorphisms of GSTM1, GSTT1, and GSTP1 polymorphisms and risk of schizophrenia.Therefore, we performed a meta-analysis on all eligible case-control studies to clarify the association between the GSTM1, GSTT1, and GSTP1 polymorphisms and schizophrenia are summarized in GSTM1, GSTT1, and GSTP1 polymorphisms were nine, eight, and four articles, respectively [The meta-analysis of this study was included 12 case and control studies. The characteristics from selected studies in ectively ,25,26,27p < 0.05 or I2 statistic was >50%. Otherwise, the fixed-effects method was adopted. For GSTM1 polymorphism, nine studies containing 2156 schizophrenia patients and 2289 control subjects were included. GSMT1 polymorphism did not show any significant association with schizophrenia . However, there was no association between, GSTT1 or GSTP1 polymorphisms and schizophrenia .To identify publication bias in meta-analysis, we evaluated publication bias using Egger’s regression. There was no publication bias  up to April 2015 without language restrictions. Relevant studies were identified using the terms: “glutathione-related enzyme” or “GSTM, or GSTT, or GSTP” and “polymorphism or polymorphisms” and “schizophrenia”. Only human studies were selected. Additional studies were identified by hand search of original or review articles. If data or data subsets were published in more than one article, only the publication with the largest sample size was included.GSTM1, GSTT1, or GSTP1 polymorphisms and schizophrenia; (2) they used a case-control study design; (3) and they contained sufficient distribution of GSTM1, GSTT1, or GSTP1 polymorphism in the schizophrenia group and the control group for the estimation of an odds ratio (OR) with a 95% confidence interval (CI).Studies were included if they met the following criteria: (1) they evaluated the association between the GSTM1, GSTT1, or GSTP1 polymorphisms.The two investigators independently extracted data and formed an analysis. When they differed in their conclusions, they rechecked the data again and reached a consensus through discussion. Data extracted from the selected articles included the first author’s name, year of publication, country of origin, ethnicity of the study population, number of cases and controls, and the genotype frequency of p value, OR and 95% CI were used to investigate the association between risk of schizophrenia and GSTM1, GSTT1, or GSTP1 polymorphisms. Firstly, we calculated the heterogeneity of studies. A χ2-test-based Q statistic test and I2 test were applied. The random-effects DerSimonian and Laird method was adopted if the result of the Q test was p < 0.05 or I2 statistic was >50%, which indicated a statistically significant degree of heterogeneity between the studies. Otherwise, the fixed-effects Mantel-Haenszel method was adopted. Publication bias was evaluated by Egger’s regression.Meta-analysis was performed using a comprehensive meta-analysis software program . The pooled GSTM1 and GSTT1 polymorphisms, the pooled ORs, 95% CI, and p value were calculated using null type versus (vs.) present type. And combination of GSTM1 and GSTT1 polymorphisms were also analyzed in meta-analysis [GSTP1, the pooled ORs were calculated for codominant 1 model , codominant 2 model , dominant model , recessive model  and allelic model . Further subgroup analysis by ethnicity, the East Asian population only included Koreans and Japanese. The value of p < 0.05 was regarded to indicate statistical significance.For meta-analysis of analysis . For GSTGSTM1 polymorphism was associated with susceptibility to schizophrenia in only East Asian population and GSTT1 and GSTP1 polymorphisms did not related to schizophrenia.


I2 = 41.4%; P = 0.043) but a non-significant result in cohort study . Additionally, significant inverse associations were observed when we carried out the stratify analyses by the study characteristics and adjustment for potential confounders among case-control studies. Given only one cohort study included in the present meta-analysis, further prospective-designed studies should validate our findings and report more detail results, including those for subtypes of fiber, the risk estimates which corrected the impact of measurement errors and fully adjust for the potential confounders.Evidence on the association between dietary fiber intake and pancreatic cancer risk has been controversial. Therefore, we carried out this meta-analysis to summarize available evidence from epidemiologic studies on this point. Relevant studies were identified by searching PubMed, Embase and Web of Science databases as well as by reviewing the rence lists of relevant articles. Random or fixed-effects model was used to calculate the summary risk estimates and 95% confidence intervals (CIs). This meta-analysis included one cohort and thirteen case-control studies which involving a total of 3287 subjects with pancreatic cancer. After summarizing the risk estimates of these studies, we yielded a significant association between dietary fiber intake and pancreatic cancer risk among case-control studies (odds ratio = 0.54; 95%CI = 0.44–0.67;  As one of the most fatal types of cancer, about 0.3 million new cases of pancreatic cancer were diagnosed and nearly the same number of patients dead from this disease in 2012 worldwideSince dietary factors may partly play a potential role in the etiology of pancreatic cancer35et al.et al.The search identified a total of 1,953 articles for which the titles and abstracts were scanned to determine potential eligibility for inclusion. After a selection process , 14 stud35678910111213141516et al.101213141516The information of study quality are summarized in 56568911101112151636101213141516versus the lowest categories of dietary fiber intake by study design are shown in I2 = 31.9%, P = 0.114). However, there is no association between fiber intake and pancreatic cancer risk in cohort study, though only one study was included (P = 0.495 for Egger’s test and P = 0.787 for Begg’s test) and qualitatively, on visual inspection of the funnel plot.The multivariable-adjusted risk estimates for each study and the summary risk estimates for the highest included . There wSince cohort study and case-control study were two different study designs and only one cohort study was found in the literature search, we excluded this cohort study in the subgroup analyses. When we carried out the stratified analysis by fiber type, significant results were observed in soluble fiber and insoluble fiber but the result showed borderline significance in crude fiber. Furthermore, I2 = 31.9%) after excluding the study by Stolzenberg-Solomon et al.I2 = 36.0%) after excluding the study by Baghurst et al.et al.I2 = 35.8%) which was similar to the main finding.In a sensitivity analysis in which we removed one study at a time and analyzed the rest, the summary risk estimates ranged from 0.53 , Embase and Web of Science databases through August, 2014 without limitations by using the following search key words: (diet or dietary or fiber or fibre) and (pancreatic or pancreas) and (cancer or neoplasm). Furthermore, bibliographies of relevant studies were hand-searched for additional publications.In this meta-analysis, we followed the guidelines developed by the Meta-analysis Of Observational Studies in Epidemiology group (MOOSE)The title and abstract of studies identified in the search were reviewed by two authors (C-HW and CQ) to exclude studies that did not answer the research question of interest. Studies considered in this meta-analysis should meet the following inclusion criteria: the study (1) had a observational study design ; (2) clearly defined dietary fiber as the exposure of interest; (3) reported pancreatic cancer as the outcome of interest; and (4) reported relative risks (RRs), odds ratios (ORs), and hazard ratios (HRs) with 95% confidence intervals (CIs) or provided data for their calculation. Inclusion was not otherwise restricted by study size, language, or publication type. If multiple articles were on the same study population, the one with more informative data was selected.versus lowest category, and factors matched by or adjusted for in the design or data analysis. From each study, we extracted the risk estimates that reflected the greatest degree of control for potential confounders. Only two studies10et al.3058914Data were independently abstracted onto a standardized form by two authors (C-HW and CQ). Conflicts in data abstraction were resolved by consensus, referring back to the original article. The following data were collected from each study: first author’s last name, year of publication, country of the study population, study design, sex, study period, number of cases and controls or cohort size, fiber intake categories and methods of dietary assessment, risk estimates with their 95% CIs for the highest The NOS includes 3 quality parameters for case-control or cohort studies: the selection of study groups, comparability of groups and ascertainment of either the exposure or outcome of interest was used by two independent researchers (C-HW and CQ) to assess study quality3233versus lowest categories of dietary fiber according to the result of heterogeneity test. In assessing heterogeneity among studies, we used the I2 statistics which values represent the amount of total variation explained by variation among studies, with a value of greater than 50% considered to indicate severe heterogeneity and a value of less than 25% indicating the absence of significant heterogeneityP < 0.1), was evaluated via Egger’s linear regressionversus hospital-based), proxy respondent (yes versus no), exposure assessment , geographic location , and confounders that were adjusted for the following: body mass index, sex, diabetes mellitus, total energy intake, and alcohol drinking. Heterogeneity between subgroups was evaluated by meta-regression. At last, we conducted sensitivity analyses by deleting each study in turn to reflect the influence of individual data sets on the overall estimate. For all tests, a probability level <0.05 was considered statistically significant. All statistical analyses were conducted by using Stata software .As the absolute risk of pancreatic cancer is low, as well as only three included case-control studies1316103236How to cite this article: Wang, C.-H. et al. Dietary fiber intake and pancreatic cancer risk: a meta-analysis of epidemiologic studies. Sci. Rep.5, 10834; doi: 10.1038/srep10834 (2015).


As an update to other recent meta-analyses, the purpose of this study was to explore whether interleukin-10 (IL-10) polymorphisms and their haplotypes contribute to tuberculosis (TB) susceptibility.We searched for published case-control studies examining IL-10 polymorphisms and TB in PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Wanfang databases and the Chinese National Knowledge Infrastructure (CNKI). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strengths of the associations.A total of 28 studies comprising 8,242 TB patients and 9,666 controls were included in the present study. There were no significant associations between the -1082G/A, -819C/T, and -592A/C polymorphisms and TB in the pooled samples. Subgroup analyses revealed that the -819T allele was associated with an increased TB risk in Asians in all genetic models  and that the -592A/C polymorphism was significantly associated with TB in Europeans under two genetic models . Furthermore, the GCC IL-10 promoter haplotype was associated with an increased risk of TB . Subgroup analyses based on ethnicity revealed that the GCC haplotype was associated with a higher risk of TB in Europeans, whereas the ACC haplotype was associated with a lower TB risk in both Asians and Europeans.This meta-analysis suggests that the IL-10-819T/C polymorphism is associated with the risk of TB in Asians and that the IL-10-592A/C polymorphism may be a risk factor for TB in Europeans. Furthermore, these data indicate that IL-10 promoter haplotypes play a vital role in the susceptibility to or protection against the development of TB. Mycobacterium tuberculosis (M. tuberculosis), is a growing global public health problem. According to the World Health Organization, approximately one-third of the world’s population is infected with M. tuberculosis, though only 10% of individuals who are infected by the pathogen will develop clinical disease [M. tuberculosis itself, the development of TB after infection may also involve certain host factors, such as host immunity and genetics [TB, an infectious disease primarily caused by genetics .M. tuberculosis persistence in humans [IL-10, which is expressed by activated monocytes/macrophages, natural killer (NK) cells, dendritic cells (DCs), mast cells, B cells, and regulatory T cell subsets, is known to have macrophage-deactivating properties and undermines the Th1-driven pro-inflammatory response by down-regulating the production of several cytokines. O'Leary et al. demonstrated that in macrophages, IL-10 may prevent phagosome maturation, thus leading to n humans . Severaln humans ,5. Furthn humans . These rThe IL-10 gene maps to chromosome 1q31-32. The IL-10 promoter is highly polymorphic, and three single nucleotide polymorphisms (SNPs) at positions -1082, -819, and -592 within the promoter region have been shown to correlate with IL-10 production . MeanwhiTo date, many genetic epidemiology studies have assessed the association between IL-10 gene polymorphisms and the risk of TB in different populations ,12–38. HMycobacterium tuberculosis’ in combination with ‘interleukin 10 or interleukin-10 or IL-10 or IL 10’ and ‘polymorphism or variant or genetic or SNP’. We also perused the reference lists of all retrieved articles and relevant reviews. If the full text article could not be obtained from the databases, we tried to contact the authors. There were no restrictions placed on language, race, ethnicity or geographic area [An elaborate search was conducted for studies that examined the association between IL-10 polymorphisms and TB . Two indhic area .Studies were included in this meta-analysis if they met the following criteria: (1) studies that evaluated IL-10 gene polymorphisms and TB risk; (2) case-control studies; (3) studies that provided sufficient data to calculate an OR and a 95% CI. Studies were excluded if they (1) contained overlapping data; (2) were based on families; (3) did not provide the numbers of null and wild-type genotypes or alleles; (4) were editorials, reviews, or abstracts; or (5) were not consistent with HWE.Data were extracted from original studies independently by two reviewers (Gao and Chen). Any discrepancies between the reviewers were resolved either by reaching a consensus or by a third reviewer (Yao). The following information was collected from each study: the name of the first author, the year of publication, the originating country, ethnicity, types of TB infection and controls, human immunodeficiency virus (HIV) status, the number of cases and controls, and genotype and allele frequency information. We verified the accuracy of the data by comparing the collection forms from each investigator.When data from at least 5 similar studies were available, meta-analysis was performed. The summary ORs and 95% CIs were used to measure the strength of the associations between IL-10 polymorphisms and TB susceptibility . The staThe heterogeneity between studies was assessed using the chi-square-based Cochrane Q-test, which was considered to be significant when P<0.10 . The fixAll statistical tests were performed using Review manager 5.2  and STATA 12.0  software. P values <0.05 were considered statistically significant.The selection process of this literature review is summarized in the flow diagram . A totalTwenty-two of the 28 articles studied the -1082G/A IL-10 polymorphism, 17 studied the -819C/T polymorphism, 16 studied the -592A/C polymorphism, and 6 studied IL-10 promoter haplotypes.The associations between the -1082G/A polymorphism and TB are shown in The survey results regarding the associations between the -819C/T polymorphism and TB are shown in Subgroup analysis by ethnicity revealed that the -819T allele was associated with increased TB risk in Asians under all genetic models . However, no association was found in Europeans or Africans under any genetic model.The results of our meta-analysis of the association between the -592A/C polymorphism and TB are shown in However, after stratification by different ethnicities, a significant association was found in Europeans using two genetic models ; this association was not observed in Asians or Africans under any genetic model.Three SNPs in the promoter region  were in complete linkage disequilibrium, and three haplotypes exist . Six of the eligible case-control studies analyzed the relationship between the IL-10 promoter haplotype and the risk of TB . The resSome intra-study heterogeneity was observed during the meta-analyses, but no evidence suggested heterogeneity between the significant associations, except for the GCC haplotype as a whole. This heterogeneity was eliminated after stratification by ethnicity. The funnel plots for these polymorphisms in all compared models were symmetrical  of the association between the -592A/C polymorphism and TB showed significant associations in Europeans. Several reasons may explain why our results differ from those of Zhang J. et al. and Liang B. et al. First, we only incorporated studies that were consistent with HWE. Second, our work was an update to the work of other groups, which allowed for the inclusion of some new studies. As a result, our conclusions may be more scientific. Taken together, our results suggest that ethnic differences may play an important role in environmental and genetic factors.We also analyzed the association between IL-10 promoter haplotypes and TB risk. In our meta-analysis of 6 studies, only the GCC haplotype was associated with an increased TB risk. Moreover, subgroup analyses based on ethnicity showed that the GCC haplotype was associated with an increased TB risk in Europeans, whereas the ACC haplotype was associated with a lower TB risk in both Asians and Europeans, suggesting that ethnic differences may play a role in the association between IL-10 promoter haplotypes and TB risk.IFNG), the vitamin D receptor gene (VDR), and the interleukin-12 p40 subunit gene (IL12B), among others [As an indispensable tool, genome-wide association studies (GWASs) are being used more and more for the identification of common variants that are associated with a variety of diseases. To date, many GWASs have successfully identified TB susceptibility genes –58. Thesg others , 57. Howg others . Many ofTwo of the selected studies in our meta-analysis considered the impact of HIV status on susceptibility to TB , 31. HowAlthough some intra-study heterogeneity was detected for these polymorphisms during the meta-analyses, no evidence of heterogeneity was found for the significant associations. After subgroup analyses by ethnicity, the heterogeneity disappeared. This suggests that ethnicity may be the main source of heterogeneity. Furthermore, we generated funnel plots and carried out Egger’s tests to evaluate the existence of publication bias; no publication bias was observed in our study.Several limitations should be considered when interpreting our results. First, additional studies are needed to complete a comprehensive analysis, especially for the IL-10 promoter haplotype . FurtherIn conclusion, this meta-analysis suggested that the IL-10-819T/C polymorphism was associated with TB risk in Asians and that the IL-10-592A/C polymorphism may be a risk factor for TB in Europeans. IL-10 promoter haplotypes play a vital role in the susceptibility to or protection against the development of TB. To further establish these associations, future studies with larger sample sizes and multi-ethnic sample groups are required.S1 File(DOCX)Click here for additional data file.S1 Meta-Analysis Checklist(DOCX)Click here for additional data file.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.


Epidemiological studies have investigated the role of choline acetyltransferase (ChAT) in Alzheimer’s disease (AD). ChAT gene polymorphisms  may be associated with the risk of AD. In this meta-analysis, we determined the relationship between the four polymorphisms and the risk of AD.We searched MEDLINE, EMBASE, and HuGEnet databases for studies linking the four polymorphisms with AD risk. We included 16 articles in our meta-analysis to assess the association between the four polymorphisms and susceptibility to AD by calculating the pooled odds ratios (ORs) and 95% confidence intervals (CIs).The combined results showed no significant association with rs1880676G/A and rs2177369G/A polymorphisms. The risk of AD  with rs868750G/A polymorphism, or the association of rs3810950G/A polymorphism with AD risk in the overall population  or Asian group  was demonstrated.Our meta-analysis suggested that rs1880670G/A, and rs2177369 G/A polymorphisms were not risk factors for AD. However, rs3810950G/A, or rs868750G/A genetic polymorphism was a genetic risk factor for the development of AD. The rs3810950G/A polymorphism had a negative effect on the risk of AD for GA or GG+GA genotypes compared with AA in the overall population or Asians. Alzheimer’s disease (AD), characterized by progressive memory loss and cognitive dysfunction, is the most common neurodegenerative disorder of unknown etiology in the elderly. The neuropathological hallmarks of the disease include deposition of plaques, neurofibrillary tangles, and progressive loss of neurons. The complex interaction between genetic and environmental factors contributes to the development of Alzheimer’s disease (AD). Choline acetyltransferase (ChAT) was found to mediate the pathogenesis of AD . Davies The ChAT gene, containing 15 exons and the entire sequence of the vesicular ACh transporter, is located on chromosome 10q11.23 –14. A laThe electronic databases MEDLINE, EMBASE, and HuGEnet were searched to identify eligible studies without language restriction. The search was only focused on “human” studies. The following Medical Subject Heading (MESH) terms or key words were used: (‘‘choline acetyltransferase” or ‘‘ChAT”) and (‘‘genetic” or ‘‘polymorphism” or ‘‘mutation” or ‘‘genes”) and (‘‘AD” or ‘‘Alzheimer’s disease”). The related reference lists were reviewed to ascertain additional studies.Eligible studies met the following criteria: (a) evaluation of 4 SNPs of ChAT gene polymorphisms  and AD risk, (b) clinical diagnosis of AD –21, (c) Two investigators independently reviewed abstracts or full text to identify eligible studies, and extracted data independently. The discrepancies were resolved following discussions. The following information was extracted: the first author, genotyping method, nation and ethnicity of the study population, year of publication, and genotype frequencies in cases and controls.The strength of the association between AD susceptibility and ChAT gene polymorphism (rs868750 G/A) was evaluated by the odds ratio (OR) and the corresponding 95% confidence interval (CI). Five different ORs were assessed in our analysis: dominant model (GG+GA versus AA), recessive model (GG versus (GA+AA), homozygote comparison (GG versus AA), and heterozygote comparison . The same method was used for the other three polymorphisms .The test for heterogeneity between studies was performed with Cochran’s Q test. A fixed effects model was used to calculate the pooled OR and 95% CI if the P-value was greater than 0.1, which indicated homogeneity . OtherwiA subgroup analysis was conducted on the basis of ethnicity or APOEε4 carrier status or ethnicity. The sensitivity analysis was performed by the sequential removal of individual studies to explore the stability of the results. The visual Begg’s funnel plot was used to explore publication bias, and Egger’s linear regression test was utilized to quantitatively assess the publication bias with STATA 12.0 software . All genA total of 114 studies were retrieved in the initial search, of which 37 related to ChAT genes and AD were identified. Based on their titles and abstracts, 21 studies were excluded because 8 were reviews, 3 studies had no controls and 10 involved cell lines. Finally, 16 studies or 26 comparisons pertaining to ChAT polymorphisms and AD risk were included. Overall, the meta-analysis of included studies comprised 1452/1175 (rs868750G/A), 3341/3013 rs1880676G/A), 1100/828 rs2177369G/A) and 3275/3878 (rs3810950G/A) cases/controls. In most77369G/A 80676G/A,heterogeneity = 0.04, random effects model. heterogeneity = 0.0003, random effects model) and the dominant model . However, the association with rs1880676G/A, and rs2177369G/A was not investigated. The details were exhibited in The relationship between rs868750 G/A polymorphism and the risk of AD was found , and the ChAT G/G genotype was associated with a higher risk for AD compared with the G/A+A/A genotypes in APOEε4 or non-APOEε4 carriers [Harold et al identified rs868750 (11604 G/A) using primer extension assay. It was localized to intron 9 or 140 bp downstream of exon 9 25]. No. No25]. Rs1880676  was identified by restriction fragment length polymorphism assay and located in exon S (D7N). If the Mubumbila et al  found SNSeveral limitations should be considered. First, the sample size of included studies was small, which might contribute to the probability of false positive or false negative results. Second, subgroup analysis based on age of onset, samples (blood or brain) or genotyping methods, which might result in selection bias and clinical heterogeneity, was not carried out due to lack of sufficient sample size. Finally, publication bias associated with the exclusion of unpublished studies with negative results was not explored.Notwithstanding the study limitations, the meta-analysis suggests that the ChAT rs1880670 G/A or rs2177369 G/A polymorphism might not be a risk factor for AD. The rs3810950 G/A or rs 868750G/A genetic polymorphism plays an important role in the development of AD, and the rs3810950 G/A polymorphism showed a negative effect on the risk of AD for GA or GG+GA compared with AA in overall comparisons or Asian populations. Further investigations into the interaction of APOEε4 carrier status or ethnicity with these polymorphisms should be carried out.S1 Table(PDF)Click here for additional data file.


I2 = 13.5%). Dose-response analysis showed linear relationship between tooth loss and risk of EC . Subgroup analysis proved similar results and publication bias was not detected. In conclusion, tooth loss could be considered to be a significant and dependent risk factor for EC based on the current evidence.Epidemiological studies have revealed the association between tooth loss and the risk of esophageal cancer (EC); however, consistent results were not obtained from different single studies. Therefore, we conducted the present meta-analysis to evaluate the association between tooth loss and EC. We conducted electronic searches of PubMed until to February 10, 2015 to identify relevant observational studies that examined the association between tooth loss and the risk of EC. Study selection and data extraction from eligible studies were independently performed by two authors. The meta-analysis was conducted using Stata 12.0 software. Finally eight eligible publications with ten studies involving 3 cohort studies, 5 case-control studies, and 1 cross-sectional study were yielded. Meta-analysis identified tooth loss increased risk of EC 1.30 times (Relative risk = 1.30, 95% confidence interval = 1.06–1.60,  When studies with overlapping data were eligible, we chose the one with the most comprehensive information. Two authors independently evaluated the eligibility of all the retrieved studies, and disagreements were resolved by discussion.For identifying relevant studies, we conducted electronic searches of the PubMed database until February 10, 2015 using the search terms  AND (dentition OR “tooth loss” OR edentulous OR “lost of tooth”). Reference lists of recent reviews and the selected papers and were manually screened to identify additional relevant studies and avoid erroneous exclusions. Only publications in English were included.Two authors independently extracted the following information from each eligible study: last name of the first author; year of publication; study design; country of origin; sample size; age; pathological characteristics of EC; unadjusted or adjusted ORs, RRs, and HRs and relevant 95% CIs or standard errors (SEs); and the covariates for the adjusted point estimates.I2 values and chi-square testI2 ≤ 50% and p > 1.0 indicated no or acceptable heterogeneityStatistical analysis was performed using STATA 12.0 software. First, we transformed ORs, RRs, or HRs and their CIs to their natural logarithms and SEs. We directly considered HR as RR720From the 155 records initially identified, 8 articles involving 3 cohort studies1727293031et al.1727293132Among the selected studies, the study of Guha I2 = 13.5%, p = 0.32), and the overall result based on the fixed effect model showed that tooth loss increased risk of EC by 1.30 times . No evidence of nonlinear relationship was detected  of heterogeneity could not be identified. Third, subgroup analyses revealed that the results are significantly inconsistent with limited statistical power owing to a relatively small number of included studies. We used Hill’s criteria to argue causality and have discussed how the results could be influenced by the sample size; greater numbers of relevant studies addressing this topic are required for enlarging the sample size. Furthermore, while almost all included studies have adjusted for smoking and alcohol consumption, other unmeasured factors, such as diabetes, gastroesophageal reflux, and socioeconomic factors may confound the interpretation of an association between tooth loss and EC and potentially introduce bias. Only a few included studies have adjusted for these factors . Fourth,In summary, the present meta-analysis indicates that tooth loss is probably a significant and dependent risk factor for EC, suggesting that people who have lost teeth should pay attention to the symptoms and avoid other classical risk factors for EC. Moreover, according to the Hill’s criteria for causal inference, tooth loss is a marker rather than causality for EC.How to cite this article: Chen, Q.-L. et al. Tooth loss is associated with increased risk of esophageal cancer: evidence from a meta-analysis with dose-response analysis. Sci. Rep.6, 18900; doi: 10.1038/srep18900 (2016).


Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants  with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans .interaction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (P Typically asymptomatic, hypertension is a major risk factor for several serious common clinical cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure . Large lACE and ABO polymorphisms [Recent genome-wide association studies (GWAS) have identified a large number of common single nucleotide polymorphisms (SNPs) associated with blood pressure  and coroorphisms .SIGLEC12 and A1BG–was associated with differences in risk among participants in the Nordic Diltiazem study who used calcium channel blockers [For the outcome of cardiovascular events, most published pharmacogenomics studies of drug-gene interactions have typically employed a candidate gene approach –12 or hablockers .We aimed to build upon prior research by more fully characterizing common variation across the entire genome and by focusing on population-based samples of treated hypertensive participants with long prospective follow-up for incident cardiovascular events. Thus, using genome-wide data on over 2 million measured and imputed SNPs from ongoing studies, this project represents a multi-center collaborative effort to identify major antihypertensive therapy-associated pharmacogenomics interactions associated with sudden death, myocardial infarction (MI) or stroke in patients with treated hypertension.The original design was a two-stage study of drug-gene interactions on the outcome of cardiovascular disease with discovery in a case-control study and replication among two cohort studies. The first stage was expected to have 1,500 cases and 2,600 controls, and the second stage was expected to have 1,250 CVD cases and 5,250 non-cases over the course of follow-up. All participants were treated for hypertension and cardiovascular disease (CVD) cases included myocardial infarction, coronary death, sudden death, and stroke. The proposed study had good power to detect modest-sized interactions with common genetic variants, for instance, 80% power to detect a multiplicative interaction of 2.3 for a variant with an allele frequency of 0.2 and a drug prevalence of 25%.During the conduct of the study, collaborations with other cohort studies and clinical trials provided an opportunity to expand the European ancestry sample size to include 3,527 CVD cases and 11,848 controls in the discovery stage and 1,751 CVD cases in the case-only replication stage. To limit genotyping costs, the design remained two-stage. Across the two stages, our study had good power to detect modest-sized interactions with common genetic variants, for instance, 97% power to detect a multiplicative interaction effect of 1.6 for a variant with an allele frequency of 0.2 and a drug prevalence of 25%.Supplementary Material  of nine studies with GWA data that included participants of European ancestry (EA) with treated hypertension in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium : the Agepressure  and coropressure  in otherWe then selected variants with the lowest p-values in Stage I for genotyping in Stage II among European ancestry participants from the Genetics of Hypertension Associated Treatment (GenHAT) ancillary case-only study of the ALLHAT clinical trial , 16. BriAlthough we did not have power for discovery analyses among non-European ancestry participants, we nevertheless conducted exploratory analyses to evaluate evidence for antihypertensive pharmacogenomic effects among African-American (AA) participants from four of the discovery studies , as well as GenHAT and the Jackson Heart Study (JHS) and to provide additional context to our discovery findings. Each study followed a pre-specified analysis protocol and findings from the within-study analyses were then combined via meta-analysis, as described below.All studies were approved by local ethics committees and all participants provided written informed consent. The ethics committees for the individual studies are: AGES: The National Bioethics Committee, Iceland; ARIC: University of North Carolina at Chapel Hill Office of Human Research Ethics; CHS: University of Washington Human Subjects Division IRB; FHS: Institutional Review Board of Boston University Medical Campus and Boston Medical Center; GenHAT: UAB Institutional Review Board for Human Use (IRB); Health ABC: clinic protocols were approved by the University of Pittsburgh Institutional Review Board and the University of Tennessee Health Science Center Institutional Review Board, and the Coordinating Center protocols were approved by the UCSF Human Research Protection Program/Committee on Human Research; HVH: Group Health Cooperative Human Subjects Review Committee; JHS: The Institutional Review Board of the University of Mississippi Medical Center; MESA: Los Angeles Biomedical Research Institute at Harbor-UCLA Human Subjects Institutional Review Board; PROSPER: Research Ethics Committee of the Cork Teaching Hospitals (CREC), Scottish Multi-Regional Ethics Committee A, and Medical Ethical Committee (METc) of the Leiden University Medical Center Rotterdam Study: Medical Ethics Committee of the Erasmus Medical Center.This study was restricted to participants with treated hypertension, defined by the use of antihypertensive medications. Participants in longitudinal cohort studies entered the cohort of treated hypertensives at the examination when antihypertensive medications were first recorded and remained in the analysis for all observations in which they were users of antihypertensives. Participants with prevalent CVD at study baseline or prior to the initiation of HTN medication were excluded.We examined four therapeutic classes of drugs: ACE inhibitors, beta blockers, calcium channel blockers, and thiazide diuretics. Drug groupings were based on manually-curated lists that were reviewed by experts from each study to include all relevant drugs from the U.S. and Europe. Participants were classified as thiazide users if they took a thiazide or thiazide-like diuretic in a single or combination preparation, with or without potassium sparing diuretic or potassium supplements. Calcium channel blockers included both long- and short-acting preparations. For primary analyses, angiotensin receptor blockers (ARBs) were grouped with ACE inhibitors.Drug exposures were assessed by medication inventory or self-report (prospective cohorts), computerized databases (HVH), or through randomized treatment assignment updated by self-report during follow-up (GenHAT). For each analysis, users of a given class were treated as the exposed group, users of all other classes served as the reference group. In this way, participants who used multiple classes of drugs appeared in multiple analyses and users were allowed to change drug classes during the course of follow-up, approximating an as-treated analysis.Supplementary Material  genotyping of selected variants was performed using a custom content on the Illumina Human Exome array. Details of genotyping and QC are provided in Supplementary Material  Cox proportional hazards regression models with time-varying antihypertensive medication exposures in which participants entered the risk set at the first known report of antihypertensive treatment, remained in the risk set for all observations in which they were users of antihypertensive medications , and were followed until their first CVD event, death, or at the date of last follow-up; (2) Logistic regression in which all hypertensive CVD cases were compared to an age and sex-matched set of population-based hypertensive controls. Supplementary Materials , and principal components for global ancestry (as needed); family based studies additionally adjusted for relatedness. Details of the software packages used to estimate cohort-specific results are shown in gc) before meta-analysis according to the genomic control method. [−8.Study-specific interaction estimates (β) and standard errors (SE) were combined by fixed effects inverse variance weighted meta-analysis using METAL.  To contr method.  The geno2 < 0.7). Using a custom-content Illumina HumanExome Chip, we then attempted to genotype these signal SNPs, along with proxies selected on the basis of GWAS associations  and 1000 Genomes linkage disequilibrium patterns.We used p-values from the Stage I discovery meta-analysis to select approximately 200 high signal markers for each of the three classes of hypertension drugs tested in the ALLHAT trial . Because beta-blockers were not a randomization group for ALLHAT (and instead were the default second-line agent), we did not pursue discovery findings from this drug class in the GenHAT case-only study. When multiple SNPs clustered at a single locus, we “trimmed” the list of SNPs on the basis of linkage disequilibrium , results from the Stage II case-only analyses were combined with the Stage I meta-analysis results in a fixed-effects inverse variance meta-analysis using METAL.We further explored top associations from the Stage I meta-analysis among African-American participants from ARIC, CHS, Health ABC, MESA, JHS and GenHAT.Table 1 and Tables A & B in S1 File. On average, participants were predominantly female and middle-aged (mean age range = 56–77 years). The estimated prevalence of drug exposure at study baseline among the EA discovery sample was highest for diuretics and lowest for calcium channel blockers (S1 File). Approximately 2 million autosomal SNPs were available for analysis after applying genotyping, imputation, and analytic quality control measures (Table D in S1 File). Q-Q plots based on meta-analyses of the cohort-specific, drug-SNP interaction parameters revealed little evidence of inflation of p-values demonstrated by lambdas less than 1.0 .We performed genome-wide association analyses across 15,375 EA participants from 9 studies to examine whether common genetic variants modified the associations between four common antihypertensive therapies and the risk of incident CVD  with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans . Characteristics of 21,267 study participants are shown in −8) for any of the four drug classes in Stage I . Thus the originally planned case-only replication effort became a second stage of discovery. However, when we combined results from Stage I and the 1,751 EA GenHAT CVD cases from Stage II, no SNP×drug interaction estimates attained statistical significance (p < 5.0×10−8) (S1 File). Further, the top ten loci from the combined Stage I and Stage II analyses showed no evidence of significance among the 4,141 African-American participants from Stage I and II (Table F in S1 File) combined. When we repeated the analyses limited to MI (rather than combined CVD) as an outcome among the EA sample, the results were similarly null . Because beta-blockers were not a first line agent in GenHAT; we did not perform a combined Stage I & Stage II meta-analysis; however, no results attained statistical significance in Stage I (Table H in S1 File).We did not detect any genome-wide significant interactions (P < 5.0×10Tables I & J in S1 File).Of the 75 well-validated GWAS variants for coronary artery disease (n = 46) and blood pressure (n = 29), 66 were directly available in our Stage I meta-analysis. Meta-analyses restricted to these 66 SNPs were similarly null  had significant, modest associations with blood pressure levels (< 1mm Hg) or with hypertension (<10% difference in risk) [While our study considered interactions between common antihypertensive medications and variants across the genome, other strategies to investigate genetic influences on blood pressure treatment have been employed with varying levels of success. For instance, the CHARGE consortium investigated 30 candidate genes that code for proteins that are direct targets of antihypertensive drugs and found that only a few (in risk) . Other sin risk) . By largin risk) , 5, 8, 9Our study focused on the major disease endpoints of MI, stroke and sudden death among treated hypertensive patients rather than the levels of blood pressure, primarily because these devastating clinical events are complications of hypertension. Because blood-pressure differences in trials of drug therapy do not translate directly into differences in the risks of clinical outcomes , we prefFor many patients, medications offer substantial benefits that can be maximized by avoiding medications in patients who are susceptible to complications or by targeting particular medications to patients who are likely to benefit. The results presented here provide little evidence that common variant alleles modify the effect of frequently-prescribed hypertension therapies on the outcomes of MI, stroke and sudden death.Although these findings do not illuminate new pathways in the risk of cardiovascular events, these null results nevertheless provide important information from the point of view of public health: our evidence suggests that there are no large common pharmacogenomic effects of blood pressure medications on CVD health outcomes; thus at this time genetic screening to guide choice of blood pressure therapy is not necessary. In conclusion, additional efforts to assemble even larger sample sizes and to more fully interrogate the human genome may be required to realize the potential of pharmacogenomics for antihypertensive drug treatment.S1 Figs(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.


We aimed to assess the effect of marine-derived n-3 PUFA on prostaglandin E2, TXB2 and LTB4 in a random-effect model. A total of 18 RCTs with 826 subjects were included in this systematic review and meta-analysis. Supplementation of marine-derived n-3 PUFA significantly decreased concentrations of TXB2 in serum/plasma in subjects with high risk of cardiovascular diseases  and LTB4 in neutrophils in unhealthy subjects (subjects with non-autoimmune chronic diseases or auto-immune diseases) . Subgroup analyses showed a significant reduction of LTB4 in subjects with rheumatoid arthritis , but not in non-autoimmune chronic disease patients . No significant publication bias was shown in the meta-analysis.A structured search strategy on PubMed, Web of Science and Cochrane up to November 2015 was undertaken in this meta-analysis. Standard mean difference was used to calculate the effect size of marine-derived n-3 PUFA on PGE2 in blood of subjects with high risk of CVD as well as LTB4 in neutrophils in unhealthy subjects, and that subjects with RA showed lower LTB4 content with supplementation of marine-derived n-3 PUFA.Marine-derived n-3 PUFA had a beneficial effect on reducing the concentration of TXB We used the following key words for the literature search: (“fish oil” OR “seafood” OR “eicosapentaenoic acid” OR “docosahexaenoic acid” OR “docosapentaenoic acid” OR “n-3 PUFA”) AND (“eicosanoids” OR “prostaglandin” OR “thromboxane” OR “leukotriene”). References of included studies were also reviewed to identify potential publications. We contacted authors for the detailed information of primary studies when possible.To identify randomized controlled studies involving the effects of marine-derived n-3 polyunsaturated fatty acids on major AA-derived eicosanoids . Studies were excluded if: subjects were diagnosed with acute disease or the duration was less than two weeks; there was dietary invention such as marine fish or others; there were other additional interventions apart from n-3 PUFA such as exercise and anti-inflammatory drugs compared with control group; data indispensable for a meta-analysis were not reported and still unavailable after contacting authors; studies with a crossover design which did not report a wash-out period; and studies which did not have a placebo group or proper control group.Search strategy and study selection were undertaken independently by two investigators, with discrepancies resolved through group discussion. Inclusion criteria were: randomized controlled trial design including parallel and crossover design; the exposure of interest was marine-derived n-3 PUFA such as EPA and/or DHA on PGE2, TXB2 or LTB4. Risk of bias table based on Cochrane Criteria was used to assess the quality of studies in the present meta-analysis, including random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), outcome data (attrition bias) and outcome reporting (reporting bias) [Extracted data from each article included the first author’s name; year of publication; study population; study design and duration of intervention; number, age, gender or sex ratio and health status in subjects; method and dose of intervention; source of samples; data of mean changes and corresponding standard deviation for PGEng bias) .2, TXB2 and LTB4 and subgroup analysis was conducted to identify the source of heterogeneity. For parallel trials, mean changes and corresponding SDs from baseline to endpoint were collected for data analysis, data was estimated according to the previous method [2, TXB2 and LTB4 and corresponding SDs at the end of two intervention periods were used in data analysis, as suggested by Cochrane handbook for Systematic Reviews of Intervention [2, TXB2 and LTB4. Heterogeneity of treatment effects between studies was tested using the Chi-square method and I2 > 50% was considered to be significant. To explore the possible influence of covariates on net changes, subgroup analyses and meta-regression were conducted to evaluate the effects of dose of total marine-derived n-3 PUFA, EPA and DHA respectively, ratio of EPA/DHA, duration and design of study, body mass index (BMI) and age of subjects and type of intervention and placebo on the overall effect size. We classified studies according to duration as short term (< 12 weeks) or long term (> = 14 weeks). Region of subjects were mainly divided into four areas- Europe, America, Australia and Asia. For the following variables—age and BMI at baseline, dose of total marine-derived n-3 PUFA, EPA and DHA, ratio of EPA to DHA, we stratified studies according to their median. Meta-regression with restricted maximum likelihood estimation was performed to evaluate the potentially important covariates exerting substantial impact on heterogeneity between the trials. According to the Cochrane Handbook for Systemic Review, publication bias was examined by using funnel plots, Begg’s test and Egger’s regression test [We conducted three independent meta-analysis for PGEs method  if SDs orvention . The metion test .The initial electronic search yielded 4107 records . Titles and abstracts were screened for 1751 citations, and 168 RCTs were obtained after eliminating other type designs. Of these, 50 RCTs were excluded because data indispensable for meta-analysis was still not available. Four studies were excluded because they only provided figures without definite information, and two studies had insufficient information (no data at baseline or endpoint). We contacteded 15 authors for data and only received replies from 4 of them, but the required data was not available. Finally, 18 studies of RCTs, including 27 study arms with 826 subjects were included in this systematic review and meta-analysis. Detailed processes of the study selection are shown in Primary characteristics of the 18 studies including 27 study arms are shown in 2, TXB2 or LTB4 at more than 2 time points, only changes from baseline to endpoint were used to calculate the overall effect size [For studies that reported values of PGEect size . For stuKnapp et al  comparedNone of the included trials reported any significant differences in characteristics of subjects in the treatment or control arm. Allocation concealment was adequate in 5 studies and unclear in others. Sixteen studies were double-blind design, one study  only mas2 [2 in plasma of healthy subjects with the supplementation of marine-derived n-3 PUFA compared with placebo supplementation .Five studies reported the effect of marine-derived n-3 PUFA on PGE2 , 25–28, 2 , 28 incl2 in subjects with high risk of CVD compared with placebo   .4 in unhealthy subjects and the other one [4 in neutrophils of unhealthy subjects compared with placebo   .4 for each potential variable including dose of total marine-derived n-3 PUFA, EPA and DHA, ratio of EPA to DHA, duration and design of study, body mass index (BMI) and age of subjects and type of intervention and placebo. Full details are shown in 4 in RA patients with supplementation of marine-derived n-3 PUFA , but not in non-autoimmune chronic disease patients  (2. The use of anti-inflammatories failed to significantly change the results for the effect of marine-derived n-3 PUFA on LTB4 (P = 0.286).Subgroup analyses and meta-regression analyses were conducted to evaluate the effects of the confounding factors on primary outcomes of marine-derived n-3 PUFA on LTB7, 0.31) . No sign7, 0.31) . There w2 concentration in mononuclear cell; special volunteers were recruited such as elite swimmers [2 and LTB4. Moreover, the studies by Mori et al [2, TXB2 and LTB4  and LTB4 in neutrophils of unhelthy subjects (P = 0.60) with supplementation of marine-derived n-3 PUFA.On the basis of funnel plots Figs  and 8 an2 in subjects with high risk of CVD and LTB4 in neutrophils in unhealthy subjects. TXB2 can induce vasoconstriction and promote aggregation of platelets as well as adhesiveness of PMNs, and LTB4 is involved in modulating the intensity and duration of inflammatory responses. On one hand, n-3 PUFAs, especially marine-derived n-3 PUFAs, directly inhibit AA metabolism to produce eicosanoids by replacing AA as the substrate, and indirectly alter the expression of inflammatory genes through effects on transcription factor genes [5 and LTE5, have slightly different structures and less potent pro-inflammatory function compared with those formed from AA [The results of this meta-analysis supported the effect of marine-derived n-3 PUFA on suppressing TXBor genes . On the  from AA . Further4 in RA patients in neutrophils with supplementation of marine-derived n-3 PUFA, Park et al [4 levels in serum of RA patients who weighed more than 55kg. For subjects with chronic diseases, the function of marine-derived n-3 PUFA did not reach statistical significance. However, PGE2 was significantly increased in hemodialysis patients compared with control group following supplementation of marine-derived n-3 PUFA [2 in mildly hypertriacylglycerolemic subjects [2 and LTB4: a decrease in proteinuria and an improvement in glomerular filtration rate was reported [5 along with decreased synthesis of the inflammatory LTB4. These eicosanoids were produced through different pathways, LTB4 was generated through lipoxygenase pathway with 5-lipoxygenases enzymes, while PGE2 and TXA2 /TXB2 were from cyclo-oxygenase (COX) pathway. So LTB5 blocked the lipoxygenase pathway and arachidonic acid was metabolized to produce PGE2 through the cyclooxygenase pathway, which led to a decrease in LTB4 and corresponding increase in PGE2.Subgroup analysis results showed a significant effect on LTBrk et al  also foun-3 PUFA , and a sn-3 PUFA . In addisubjects . A hypotreported , which m2 showed a reduction with supplementation of marine-derived n-3 PUFA in populations with high risk of CVD. Mehta et al. [2 in Barrett’s mucosa. This study also suggested no significant alteration in AA and increase in phospholipase A2 activity. Hishinuma et al. [2 > PGF2α > TXB2 > 6-keto-PGF1α [2 and a reduction in TXB2 concentration.However, for another product of the cyclooxygenase pathway, TXBa et al.  found tha et al.  demonstrto-PGF1α , 44 when4 and PGE2 were found, but there was a remarkable increase in the amounts of EPA and DHA as well as their potent bioactive products including resolvins and protectins , and the less potent products including LTB5 and PGE3. The author assumed that marine-derived n-3 PUFA exerts anti-inflammatory functions by the potent bioactive rather than AA-derived eicosanoids. This hypothesis could explain why there was no difference in PGE2 levels after marine-derived n-3 PUFA supplementation, but this conflicted with our results for TXB2 and LTB4. The inconsistency may be most likely due to the difference in the ratio of n-3/n-6 PUFA. In the study by Kang et al [2, TXB2 and LTB4. More animal experiments are needed to explore the mechanism of how marine-derived n-3 PUFA exerts its effect on inflammation.An animal experiment by Kang et al  examinedng et al , the n-32 [2 tended to decrease with n-3 PUFA supplementation in both groups, but this did not reach statistical significance. It was most likely due to the low production of eicosanoids at baseline in healthy subjects. However, Andrade et al. found swimming athletes who had supplementation of marine-derived n-3 PUFA showed decreased PGE2 in plasma [2 in mononuclear cell (MNC) [2 and TXB2 may result from the different dose of n-3 PUFA. Individuals with a higher concentrations of EPA and DHA into erythrocyte membranes also showed the greatest reduction in erythrocyte AA content [2 production [In healthy subjects, marine-derived n-3 PUFA supplementation had no significant effect on TXB2 , 24, whi2 , who foun plasma , which wn plasma , and EPAll (MNC)  and skinll (MNC) . The dif content . A substoduction .2 were measured in plasma of healthy subjects, and TXB2 were tested in in serum/plasma in subjects with high risk of CVD , and subgroup analyses were conducted to evaluate the effects of confounding factors on overall effect size of LTB4 in unhealthy subjects. In addition, we discovered the effects of marine-derived n-3 PUFA on PGE2 and TXB2 were different, and future studies can recruit volunteers with different health status to explore the effect of n-3 PUFA on eicosanoids. Lastly, no significant publication bias was shown in the meta-analysis according to the results of funnel plots and Egger’s test.We first utilized pooled data to quantitatively assess the effect of marine-derived n-3 PUFA on AA-derived major eicosanoids , ‘shared’ control group was split into two or more control groups to couple the intervention group according to the method by Cochrane handbook . Studies2 content in subjects with high risk of CVD and LTB4 concentrations in unhealthy subjects. Subgroup analyses showed that marine-derived n-3 PUFA significantly decreased LTB4 in RA patients, but not in non-autoimmune chronic disease patients, and duration of intervention with marine-derived n-3 PUFA also affected the overall effect size. High quality RCTs are needed to explore the effects of marine-derived n-3 PUFA on different eicosanoids in subjects with different health status.In conclusion, this systematic review and meta-analysis provided evidence that marine-derived n-3 PUFA had a significant benefit on the reduction of TXBS1 PRISMA Checklist(DOC)Click here for additional data file.S1 Fig(DOC)Click here for additional data file.


Background. Acute coronary syndrome (ACS) has an important impact in public health with high morbidity and mortality. Prothrombotic and proinflammatory states are involved in the pathogenesis of the disease. Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of the fibrinolysis and also is part of immune response. The -844 G>A gene polymorphism is related to increased PAI-1 protein levels. The aim of the study is to evaluate the association of -844 G>A PAI-1 polymorphism with ACS. Methods. A total of 646 individuals were recruited from Western Mexico: 350 unrelated healthy subjects and 296 patients with diagnosis of ACS. Results. The most important risk factor in our population was hypertension, followed by smoking. The genetic distribution showed an association of the A allele  and AA genotype  with ACS. The recessive model displayed similar results . As additional finding, we observed significant differences in the genetic distribution of ACS dyslipidemic patients . The A allele and AA genotype of -844 polymorphism of PAI-1 gene are risk factors for ACS. The AA genotype might be associated with the development of dyslipidemia in ACS patients. Acute coronary syndrome (ACS) is a growing concern around the world, a leading cause of death, and an important cause of disability , 2. It iACS is a complex disease in which environmental and genetic factors play an interrelated role in its progress. It begins with an altered lipid metabolism and an inflammatory response, followed by the development of an atherosclerotic plaque. Nevertheless, in most cases the rupture of the plaque, formation of a thrombus, and the vessel lumen occlusion are required to trigger the acute myocardial event .The haemostatic system is a key contributor of the thrombogenesis. It is widely known that multiple genes modulate the coagulation-fibrinolysis balance; therefore they could have an implication in the atherothrombotic vulnerability . The bioPAI-1 gene is part of the serpine superfamily. It is located in 7q21.3-q22 and contains 9 exons . The encThere is increasing evidence which indicates that higher levels of PAI-1 are an independent risk factor for the development of vascular disease, including cerebrovascular and cardiovascular disease , 9. MoreThe aim of the present work is to analyze the association of the polymorphism -844 G>A with ACS in Western Mexican population.The study consisted in a total of 646 individuals from Western Mexico, divided into two different groups: 296 ACS patients and 350 healthy subjects (HS). ACS patients were diagnosed in accordance with the criteria of the American College of Cardiology (ACC) . The medAll the subjects were age-matched and recruited from the Hospital de Especialidades del Centro Médico Nacional de Occidente del Instituto Mexicano del Seguro Social (CMNO-IMSS). Only those individuals who for three generations, including their own, had been born in Western Mexico were considered.All subjects and patients agreed to participate and signed an informed written consent. The study was performed in accordance with the ethical guidelines of 2013 Declaration of Helsinki and with the approval of the ethics committee of the Centro Universitario de Ciencias de la Salud, UdeG (C.I. 069-2012).μL containing 1 μg of gDNA, 1.25 U/μL of Taq DNA polymerase (Invitrogen Life Technologies), supplied buffer enzyme 1x, 20 μM of each oligonucleotide, 2.5 mM of MgCl2, and 2.5 mM deoxynucleotide triphosphate (dNTP Invitrogen Life Technologies).Genomic DNA was extracted from peripheral blood according to salting out method . The ana XhoI restriction enzyme . The G allele generates an XhoI restriction site (5-′C/TCGAG-3′) which results in the production of two fragments of 364 and 146 bp. The -844 G>A PAI-1 polymorphism was analyzed by silver stained polyacrylamide gels . For the quality control of genotyping, one random sample of each homozygote genotype was made by automatized sequencing method .The thermocycling conditions had an initial denaturation step of 3 min at 94°C, followed by 30 cycles of 20 s each at 94°C, 57°C, and 72°C, with a final extension step of 1 min at 72°C. PCR products of 510 base pairs (bp) were digested for 1 h at 37°C with 3 U oft-test, ANOVA) and nonparametrical tests . Qualitative data and Hardy-Weinberg equilibrium were analyzed with χ2 test or Fisher's exact test, when applicable. Allele frequencies were determined by counting method. Dominant and recessive allele models were tested with χ2 test. The significance level was <0.05. The measure of association was odds ratio (OR). Bivariate and multivariate logistic regression analyses were accomplished to adjust the risk for every independent variable and to know the risk of polymorphism with ACS. Independent variables were categorized by risk factors, including diabetes, hypertension, smoking, dyslipidemia, and obesity.SPSS statistical package version 20.0, Excel 2010, and Genetic Data Analysis  were useThe sample size was calculated based on the minor allele frequency of the -844 G>A PAI-1 polymorphism reported in Mexican Mestizo population by Padilla-Gutiérrez et al.  and we oHS and ACS patients groups had a mean age of 56.7 years (±8.3 SD) and 62.91 (±11.81 SD), respectively. As it is depicted in The most prevalent risk factor was hypertension, followed by smoking and type 2 diabetes (DM2). Treatment included administration of antiplatelet , heparin, statins (atorvastatin), and antihypertensive drugs.Analysis of the -844 G>A Polymorphism. The HS group was in Hardy-Weinberg equilibrium (P = 0.29). We compared the HS frequencies with other populations. The A allele prevalence was 23% in Sub-Saharan African, 27% in Mexican, 28% in Afro-American, 41% in Hispanic, 49% in Asian, and 56% in European populations [P < 0.01).ulations , 18. TheP = 0.04) and the AA genotype  were more prevalent in ACS contrasted to HS group. We also included dominant and recessive models in the analysis. In the former model no association was found, whereas recessive model showed a significant association .Allele and genotype frequencies were compared between HS and ACS groups . The disP = 0.04) in the recessive model. The variables overweight/obesity, DM2, dyslipidemia, and HBP were analyzed by logistic regression with a recessive model as dependant variable, keeping their significance in ACS dyslipidemic patients with the AA genotype (P = 0.04). No differences were found among genetic frequencies in other characteristics.Furthermore, ACS group was stratified by genotype and used to evaluate the most common risk factors and other characteristics . We founAtherothrombotic and neovascularization process are important mechanisms of cardiovascular disease in ACS. As highlighted above, PAI-1 molecule participates in both processes . RelevanThe age and gender are the most important factors for ACS, in which an advanced age and male sex are considered with an increased risk . In our The most common risk factor among our population was HBP, followed by smoking, DM2, and dyslipidemia. In opposition with our findings, RENASICA study displayed the prevalence of smoking above HBP . An explAs it was established previously, we found differences in the genetic distribution in the HS group compared with other populations, including Europeans, Asians, and Sub-Sahara Africans, but not with the African American group and a previous report of Western Mexicans . The ownP = 0.04). The AA genotype carriers had 1.86 more susceptibility to ACS . In accordance with the genetic models, two copies of the A allele are required to modify ACS susceptibility .In our study, we found an association of -844 G>A polymorphism with ACS. The A allele was 1.27 times more frequent in patients than HS (36.7 versus 31.3%, OR = 1.27, PAI-1 is a remarkable molecule which modulates the development of atherosclerosis and cardiovascular disease , 24. IntThe base change of G for A in position -844 has been associated with different diseases, including venous thrombosis, preeclampsia, stroke, rheumatoid arthritis, systemic lupus erythematosus, metabolic syndrome, and myocardial infarction. The involvement in vascular, metabolic, inflammatory, and/or thrombotic systems is connection between these diseases and ACS , 28–30.Furthermore, previous reports supported the relationship existing between -844 G>A polymorphism and plasmatic PAI-1 levels, where A allele and AA genotype are associated with superior amounts of protein , 31, 32 In addition, the recessive model indicated a greater risk of ACS patients to have dyslipidemia in AA genotype carriers in comparison to AG and GG genotypes, which suggest the necessity of both alleles to modify dyslipidemia risk. In 2002, Haselbauer and collaborators did not find an association of the -844 G>A polymorphism with coronary artery disease or myocardial infarction; however the Gensini Score, which evaluates the collateral circulation of coronary arteries, was higher in carriers of AA genotype in patients with unfavorable lipid profile . de la CThe AA genotype carries of the -844 G>A PAI polymorphism have 1.86 more susceptibility to develop SCA. Also, under the recessive genetic model this polymorphism was associated with dyslipidemia in SCA.