In order to shed a light on these inconsistent findings and to clarify the role of mbl2 polymorphisms in susceptibility or progression of chronic hepatitis B (CHB), a meta-analysis was performed.The results of studies on the relation between Mannose-binding lectin gene (mbl2 polymorphisms and chronicity or progression of hepatitis B infection. Odds ratio (OR) and its 95% confidence interval (CI) served as indexes.PubMed and Embase were searched for available articles. A meta-analysis was performed to examine the association between mbl2 exon1 polymorphisms and CHB risk in any genetic model or pairwise comparisons when compared with HC group or SR group. In the stratified analysis of ethnic groups, also no obvious relation between mbl2 polymorphism and CHB risk was identified. There was still no significant association between the complete mbl2 genotypic profile (including both the exon1 and the promoter gene) polymorphisms and CHB risk, as compared with SR group. However, it was found that there was an association between the mbl2 AO/OO genotype and severe hepatitis B (SHB) or liver cirrhosis (LC) , but there was no relationship between the mbl2 AO/OO genotype and hepatocellular carcinoma (HCC) .A total of 17 eligible studies were involved, including 2151 healthy controls (HC), 1293 spontaneous recovered (SR) patients with acute infection, 2337cases with chronic hepatitis B (CHB) and 554 cases with progressive hepatitis B. There was no evidence of significant association between mbl2 exon1 polymorphisms might not significantly associate with chronicity of HBV infection, but might be significantly related to the progressive HBV such as SHB and LC.The present meta-analysis indicated that  Hepatitis B virus (HBV) infection leads to a wide spectrum of clinical presentations from inapparent infection to self-limiting acute hepatitis, chronic infection, fulminant hepatic failure (FHF), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) . The mecMannose-binding lectin (MBL) is an important constituent of the human innate immune system, which, as an acute-phase reactant, is secreted by the liver. MBL is a calcium-dependent C-type lectin with a structural analogy of complement component C1q. MBL can bind through multiple lectin domains to the carbohydrate moieties expressed on the surface of many microbial organisms, and activate macrophages and the complement system cascade . It is ambl2) have been shown to affect the oligomer formation and circulating levels of MBL [mbl2 gene give rise to amino acid substitutions within the collagen-like region of MBL. These three polymorphic alleles are collectively designated as allele O, while the wild-type structural allele is described as allele A [mbl2 at positions 221 Y/X [mbl2 and CHB [mbl2 mutations are prone to developing persistent HBV infection and that the MBL plays an important role in the clinical outcome after HBV infection [mbl2 polymorphisms may be an important factor in determining the prognosis in patients with hepatitis B virus infection [Polymorphisms in the MBL gene  were searched independently by two investigators (Hangdi Xu and Mingfei Zhao). The search terms were the following key words: (“Mannose binding lectin” or “Mannose binding protein” or “Mannose-binding lectin” or “Mannose-binding protein” or “MBL2” or “MBP2” or “MBL-2” or “MBP-2”), and (“HBV” or “Hepatitis B”). The search strategy was shown in In order to collect all papers involved in mbl2 polymorphisms and HBV infection; (2) a case-control or cohort studies; (3) sufficient genotype data for calculating the odds ratio (OR) with 95% confidence interval (CI). The criteria of excluding studies were following: (1) the studies with overlapped data; (2) abstracts, comments, reviews or editorial letters.The criteria of collecting the published studies were following: (1) the evaluation of the association between The following information was extracted from each study: the first author’s name, years of publication, ethnicity of population, numbers of cases and controls, genotyping methods, genotyping results of cases and controls, and the Hardy-Weinberg equilibrium (HWE) results. The control groups included healthy control (HC) groups and spontaneous recovered (SR) groups with acute infection.HC were negative for hepatitis B surface antigen (HBsAg) and HBV DNA. The spontaneously recovered (SR) individuals were positive for both hepatitis B surface antibody and hepatitis B core antibody, but definitely negative for HBsAg; or positive for HBsAg and IgM anti-HBc on presentation and clearing HBsAg within 6 months. CHB individuals were with persistent HBsAg positive for more than 6 months. SHB patients had severe liver disease symptoms, including obvious clinical manifestations and conspicuous changes in their biochemical parameters, such as significant serum alanine aminotransferase (ALT) elevation  and plasma prothrombin activity (PTA) <60%. LC subjects were defined as HBsAg carriers whose liver ultrasound scan or liver function test confirmed cirrhosis. HCC patients were diagnosed by serum α-fetoprotein levels and hepatic arteriography or histology.2 or Fisher’s exact test) and a P < 0.05 was considered as significant disequilibrium. OR and the corresponding 95% CI were utilized to evaluate the strength of association of mbl2 polymorphisms with CHB. Quantitative meta-analysis was performed using STATA version 10.0 . Heterogeneity was assessed for each study using Cochrane’s Q-test and I2 measurement . P ≤ 0.10 or I2 ≥ 50% indicated that the heterogeneity was significant. A random effect model was used in the presence of substantial heterogeneity. The potential risk of publication bias was examined by the Egger test, and P ≤ 0.10 indicates the presence of a publication bias. Subgroup analysis was also performed for ethnicity and the types of progressive hepatitis B virus infection. Sensitivity analysis was conducted to evaluate the validity and reliability of primary meta-analysis. Nonsuperiority test was used to confirm the absence of association between mbl2 exon 1 polymorphism and persistence of HBV infection.First of all, HWE was assessed in the HC groups using the goodness-of-fit test . The publication bias of these studies was assessed by Egger’s test. In HC groups, the funnel plot showed the asymmetry in mbl2 exon1 OO vs. AA and AO+OO vs. AA models to some extent, and Egger’s test proved the existence of publication bias in these two models . No significant publication bias was detected in other comparisons.Ten studies ,19,22,23mbl2 O allele carriers (AO and / or OO) in both Asian populations and non-Asian populations were not associated with the increased risk of chronic HBV infection as compared with HC or SR groups, respectively  (Four studies with SR groups and two studies with HC groups about association between reported . The res42-1.51) . When an42-1.51) .mbl2 genotypic profile including both the exon1 and the promoter polymorphisms. Although only four studies reported such data .Subsequently, a meta-analysis was performed on the studies that reported a complete uch data , it was mbl2 wild type versus mbl2 variant (AO/OO) genotype. As the HC group in the study of Hakozaki Y et al [mbl2 genotypes AO/OO were significantly related to HBV progressive liver diseases . As the progressive liver disease contains three types of diseases , the association between mbl2 exon1 polymorphisms and the risks of each hepatic disease was investigated. The results . However, the significant association between mbl2 AO/OO genotypes and HCC was not observed .There were six studies on hepatitis B progression with the sufficient data of  Y et al  was not  results  demonstrNon-superiority test was performed to confirm the absence of association between MBL2 polymorphism and persistence of HBV infection. The null hypothesis is that the frequency of MBL2 exon1 O alleles in CHB patients is greater by Δ as compared with the frequency in controls. The specified amount Δ may be arbitrary, and it may be taken from the lower boundary of the difference estimated in the initial report of the genetic association ,28. The P-values for MBL2 exon1 was 0.0005 and 0.0012, as compared with HC or SR respectively, which support the absence of association between MBL2 exon1 polymorphism and persistence of HBV , more studies should been taken to verified this result in the future.MBL is an innate immune system pattern recognition protein which can kill the different pathogenic microbes through complement activation. The  disease ,30. Our placenta . Thus, tplacenta . The resmbl2 genotypic profile, including promoter region and structural region. No significant association between complete mbl2 genotype and CHB susceptibility was found, as compared with SR group.In order to investigate these alternative results, the additional ad hoc meta-analysis was performed for the studies that reported complete mbl2 variant genotypes (AO/OO) and SHB or LC. It was concluded that MBL would not appear to be involved significantly in host susceptibility to CHB, but might play an important role in exacerbation and progression of hepatitis B. These genotypes (AO/OO) might be associated with the natural wound healing process, which may develop the necroinflammation, rather than carcinogenesis [Our meta-analysis demonstrated that there was the significant relation between ogenesis ,17.mbl2 AO/OO genotypes were more likely to develop the symptomatic cirrhosis and severe hepatitis.The progression of HBV infections resulted from MBL mutations may be explained by two possible mechanisms. Firstly, MBL may have a direct effect on HBV infection through complement activation. The amannose-rich oligosaccharide was detected in the preS2 region of the hepatitis B surface protein, so MBL could bind HBV in theory ,32. Morembl2 polymorphisms, there are still some limitations that should be taken in to account when interpreting our results. Heterogeneity and confounding factors may have affected the meta-analysis. The moderate and high heterogeneity existed in the analyses, especially in the subgroup of Asians or the SHB group. Publication bias may be other influence factor of this meta-analysis. It is possible that the studies with negative results have not been published, and Egger’s test indicated that the publication bias existed in two contrasts when CHB group was compared with the HC group. Furthermore, there was only a small amount of data in present meta-analysis, especially in some subgroup analysis.In spite of providing the most comprehensive assessment of the association between the outcome of HBV infection and the mbl2 polymorphisms and the HBV infection was systematically analyzed in present meta-analysis. The combined results showed that mbl2 exon1 polymorphisms might be not significantly associated with chronicity of HBV infection, but might be significantly associated with the progressive HBV such as SHB and LC. Moreover, mbl2 polymorphisms might be not significantly associated with carcinogenesis of CHB. Since the potential confounders could not be ruled out completely and the studies in subgroup analysis were limited, it is necessary to confirm these results with more studies in future.In summary, the association between the Table S1Distribution of MBL2 exon1 genotypes among HBV cases and controls in the meta-analysis.(DOC)Click here for additional data file.Table S2Distribution of MBL2 promoter genotypes among HBV cases and controls in the meta-analysis.(DOC)Click here for additional data file.Table S3Distribution of polymorphisms of MBL2 promoter plus exon1 among HBV cases and controls in the meta-analysis.(DOC)Click here for additional data file.Table S4Non-superiority tests of mbl2 polymorphism in CHB as compared with HC.(DOC)Click here for additional data file.Table S5Non-superiority tests of mbl2 polymorphism in CHB as compared with SR.(DOC)Click here for additional data file.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


Forty-four (48%) of 109 patients were on immunosuppressive therapy and 38/109 (35%) on systemic glucocorticoid therapy. The agreement between the IGRAs was substantial (κ = 0.71) whilst that between the IGRAs and TST was low (κ = 0.32). Logistic regression models revealed that IGRAs associated with risk factors for latent tuberculosis infection better than TST. TST was influenced by age, BCG vaccination, sex, and glucocorticoid therapy. We found that IGRAs performed equally well with low level of indeterminate results (1-2%). IGRAs were superior to TST because the latter was influenced by BCG-vaccination status and immunosuppressive therapy.The performance of the interferon gamma release assays (IGRAs) and tuberculin skin test (TST) was reviewed retrospectively in patients with psoriasis, inflammatory musculoskeletal diseases, or miscellaneous inflammatory conditions. The study was carried out over a 22-month period using 109 records of patients with psoriasis ( The risg agents , which hsk of TB . In coun therapy . γ (IFNγ) release assays (IGRAs), namely, T-SPOT.TB  and QuantiFERON-TB Gold In-Tube , have been developed. Both utilize the ability of sensitized T lymphocytes to release IFNγ upon stimulation with synthetic peptides specific to Mycobacterium tuberculosis. These methods show superior diagnostic accuracy in comparison to the tuberculin skin test (TST) [Two commercial interferon-st (TST) .The present retrospective study aimed to investigate associations between the risk factors for LTBI, vaccination status, or prior immune suppression and the results of the two commercially available IGRAs, which were appropriately modified, and TST in patients with psoriasis and inflammatory musculoskeletal diseases.Mycobacterium tuberculosis, ongoing use of glucocorticoids, immunosuppressive drugs, and/or biologicals. We divided patients into three categories according to their diagnoses  adopted for both methods in our laboratory. For each test we developed an internal quality control sample, that is, the preparation resembling the actual clinical sample that was divided into aliquots and assayed regularly.TB was modified and validated as earlier described [6 lymphocytes, and the lymphocyte count from isolated PBMC preparation is calculated with an automated hematologic analyzer  for cell quantification and purity assessment; (ii) an additional positive control, that is purified protein derivative (PPD)  that was used with each sample; (iii) the analysis is performed in duplicates.The commercial T-SPOT.escribed . Brieflyγ  by that of PeliKine Compact human EIA . The latter gave a steeper calibration curve and ensured more accurate result interpretation in the cutoff zone [The B-TbIFNg is a modified version of the QuantiFERON-TB Gold In-Tube . The majoff zone .6 lymphocytes. However, to make the results comparable with other studies, the calculations were based on the cut-offs defined by the manufacturer, that is 0.35 IU/mL and 25 reactive cells/106 lymphocytes, equal to 6 spots/well.Based on our imprecision study and a pilot evaluation , 9, we uTST was performed by properly trained operators with 2 TU of purified protein derivative  according to the Mantoux technique on the surface of the forearm. The result was recorded after 48–72 h, and induration ≥10 mm was used as a positive result.In the absence of the “gold standard,” we evaluated the performance of Ly-TbSpot, B-TbIFNg, and TST and assessed the results according to the presence of any risk factor for LTBI: history of active tuberculosis, birth in an endemic country, or a history of a close TB contact. Chest X-ray finding suggestive of a history of TB was primarily considered as a risk factor but was omitted from the index because (i) it was associated with odds less than 1 for positive test results; (ii) when the chest X-ray findings indicated LTBI, IGRA and TST were often not requested by physicians.P < 0.1 in the univariate analyses and independent from each other were included.The odds ratios for positive test results were calculated with univariate logistic regression. We evaluated the results in association with an attribution to a group that is, each result was compared to all other results and to potential confounding factors such as age, sex, BCG-vaccination status and medications. Covariates with significance of P-values were two sided.Cohen's kappa statistic was used to assess the agreement between the tests. We used logistic regression for the analysis of factors contributing to concordance and discordance between tests pairwise. All n = 46 (42%)). Six (6%) patients were on anti-TNFα blocking therapy. Ly-TbSpot test was performed in 98, B-TbIFNg in 71, and TST in 80 patients, respectively  than men, also in multivariate analysis.The risk factor analysis revealed that those being born in endemic country or having a history of contact or previous TB had higher odds for positive Ly-TbSpot , that is patients with negative TST were older (mean 65.9 years) than those with positive TST (52.4 years). Also BCG vaccination correlated moderately with TST . Females had lower odds for positive TST, OR 0.2 (P < 0.01), than men. Group 3 had lower odds for positive test results compared with the other groups, although the number of TST performed was lower in this group , but this effect was not confirmed in multivariate analysis (data not shown).We found an association between TST positivity and birth in TB-endemic country, sex, and inclusion in group 3. As age and BCG vaccination status were not independent, they were included as covariates separately, both showing significant association with test results. Ongoing glucocorticoid therapy had an effect on TST, OR 0.3  (κ = 0.24–0.32). When the concordance of the tests was assessed for each group separately, the conclusion drawn for the whole cohort held true also for each group (data not shown).The IGRAs produced highly concordant results ( = 0.71) . On the The rates of indeterminate results were 2/98 (2%) and 1/71 (1.4%) for Ly-TbSpot and for B-TbIFNg, respectively. As to the former, both patients had lymphopenia. In one of them, although the B-TbIFNg test was negative showing an acceptable PHA reactivity, we doubted its validity because this method provides neither visual assessment nor lymphocyte normalisation, as for example, Ly-TbSpot. In one patient, the B-TbIFNg was indeterminate due to nonsufficient PHA reactivity but the same sample tested in Ly-TbSpot was acceptable because the reactivities both to PHA and PPD were sufficient.ex vivo function of lymphocytes in IGRA tests. Indeed, in our practice the rates of indeterminate results were very low and were mainly attributed to lymphopenia. In our laboratory, EIA-based methods performed equally well as the ELISPOT method, although EIA-method measures only the bulk of excreted interferon gamma and does not allow visual assessment of the quality. The good performance may be partly attributed to the EIA reagents from another manufacturer providing a steeper calibration curve, which makes the reading and interpretation more reproducible at the cut-off zone [Here, we present findings that are not consistent with some previous studies , 11. We off zone . There are several studies where the IGRAs have been compared in rheumatic and psoriatic patients . Of note, this risk factor did not emerge in the TST analysis (OR 1.2: 95 CI% 0.2–12). Furthermore, birthplace outside Finland  emerged as a trend for a positive TST result whereas for the IGRAs this factor was less strongly associated. It is of note that our participants were heterogeneous in relation to the factor of birthplace: only 5/12 persons were born in highly endemic countries as defined by WHO . Of the ex vivo stimulation [The correlation between partial TB treatment and a positive IGRA test is expected. Tapaninen et al. have observed that even complete three-drug antituberculosis regimen given decades ago may not lead to the complete attrition of earlier sensitized lymphocytes that may recognize cognate antigens upon new mulation . For thaThe results of the present study encourage us to recommend EIA-based techniques throughout Finland and to other areas, where the sample transportation is challenged both by long distances and changes in temperature in the north temperate zone. This method can be applied to LTBI diagnostics in the majority of cases in whom systemic biological drugs are indicated. IGRA-based methods are of no doubt superior to TST because in contrast to TST, IGRAs provide negative result that can be distinguished from a false negative result due to immunological anergy, a feature of extreme importance when testing immunosuppressed patients. We are not in favour of simultaneous TST and IGRA testing for the screening of LTBI in patients with autoimmune conditions as suggested by Bartalesi et al. . In thei In the present study B-TbIFNg and Ly-TbSpot proved to be methods of choice in evaluation of LTBI.


MYLIP region in the Mexican population in order to fine-map the actual susceptibility variants of this locus. The p.N342S polymorphism was identified as the underlying functional variant accounting for one of the previous signals of genome-wide association studies and the N342 allele was associated with higher cholesterol concentrations in Mexican dyslipidemic individuals. To date, there is no further evaluation on this genotype-phenotype association in the literature. In this scenario, and because of a possible pharmacotherapeutic target of dyslipidemia, the main aim of this study was to assess the influence of the MYLIP p.N342S polymorphism on lipid profile in Brazilian individuals.A recent study investigated the MYLIP rs9370867  polymorphism were detected by high resolution melting analysis.1295 subjects of the general population and 1425 consecutive patients submitted to coronary angiography were selected. General characteristics, biochemical tests, blood pressures, pulse wave velocity, and coronary artery disease scores were analyzed. Genotypes for the MYLIP rs9370867 genotypes with lipid profile, hemodynamic data, and coronary angiographic data was found. Analysis stratified by hyperlipidemia, gender, and ethnicity was also performed and the sub-groups presented similar results. In both general population and patient samples, the MYLIP rs9370867 polymorphism was differently distributed according to ethnicity. In the general population, subjects carrying GG genotypes had higher systolic blood pressure (BP), diastolic BP, and mean BP values  compared with subjects carrying AA genotypes  , even after adjustment for covariates. However, in analysis stratified by ethnicity, this finding was not found and there is no evidence that the polymorphism influences BP.No association of the MYLIP variant can present distinct results according to the studied population. In this moment, further studies are needed to reaffirm if the MYLIP p.N342S polymorphism is functional or not, and to identify other functional markers within this gene.Our findings indicate that association studies involving this  Lipid profile disorders have been significantly associated with risk of cardiovascular disease (CVD), which is also influenced by genetic factors, hypertension, type 2 diabetes mellitus, obesity, and smoking. CVD are the main cause of morbidity and mortality in developed countries and the financial cost is enormous. Thus, guidelines from the National Cholesterol Education Program (NCEP) rely on low-density lipoprotein cholesterol (LDL-C) for the prevention of CVD -6.A conventional lipid panel reports several parameters, including total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Of these, the NCEP and the American Heart Association recommend using LDL-C as a primary target of therapy in conjunction with assessing cardiovascular risk factors. The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults  updated clinical guidelines for cholesterol testing such as high TC (≥ 240 mg/dL), high LDL-C (≥ 160 mg/dL), and low HDL-C (< 40 mg/dL) ,7,8.MYLIP gene that were associated with LDL-C concentrations [MYLIP functional variant and the mechanistic basis of these associations were recently postulated by Weissglas-Volkov et al. [Population genetic and epidemiological studies could help to assess the etiologic role of lipid profile in CVD and, novel genetic determinants of blood lipids can also help to provide new insights into the biological pathways and identify novel therapeutic targets. In this way, current genome-wide association studies (GWAS) have identified genetic loci contributing to inter-individual variation in serum concentration of lipids -12. Sometrations . The MYLv et al. .MYLIP gene encodes a regulator of the LDL receptor pathway for cellular cholesterol uptake called MYLIP . Weissglas-Volkov et al. investigated the MYLIP region in the Mexican population in order to fine-map the actual susceptibility variants. They identified the rs9370867 non-synonymous polymorphism (p.N342S) as the underlying functional variant accounting for one of the previous GWAS significant signals and associated N342 allele with higher TC concentrations in Mexican dyslipidemic individuals [ividuals .MYLIP p.N342S – lipid profile). In this scenario, the main aim of this study was to assess the influence of the MYLIP polymorphism on lipid profile in Brazilian individuals.To date, there is no further evaluation on this genotype-phenotype association , Sao Paulo, Brazil. All patients had a clinical diagnosis of angina pectoris and stable angina. No patient enrolled in this study was currently experiencing an acute coronary syndrome. Patients with previous acute ischemic events, heart failure classes III–IV, hepatic dysfunction, familiar hypercholesterolemia, previous heart or kidney transplantation, and in antiviral treatment were excluded -19. PatiPardo in Portuguese), Black, Amerindian or Oriental descent [Weight and height were measured according to a standard protocol, and body mass index (BMI) was calculated. Individuals answered a clinical questionnaire that covered questions regarding smoking status and current medical treatment. Individuals who had ever smoked more than five cigarettes per day for the last year were classified as smokers ,20. Ethn descent ,21,22.Triglycerides (TG), TC, HDL-C, LDL-C, and glucose were evaluated by standard techniques in 12-h fasting blood samples. Diabetes mellitus was diagnosed by the presence of fasting glucose ≥ 126 mg/dL or the use of antidiabetic drugs . HyperliBlood pressure was measured in the sitting position with the use of a standard mercury sphygmomanometer on the left arm after 5 min rest. The first and fifth phases of Korotkoff sounds were used for systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. The SBP and DBP were calculated from two readings with a minimal interval of 10 min apart. Hypertension was defined as mean SBP ≥140 mmHg and/or DBP ≥90 mm Hg and/or antihypertensive drug use . The meaCarotid-femoral pulse wave velocity (PWV) was analyzed with an automatic device  by an experienced observer blinded to clinical characteristics. Briefly, common carotid artery and femoral artery pressure waveforms were recorded non-invasively using a pressure-sensitive transducer . The distance between the recording sites (D) was measured, and PWV was automatically calculated as PWV = D/t, where (t) means pulse transit time. Measurements were repeated over 10 different cardiac cycles, and the mean was used for the final analysis. The validation and its reproducibility have been previously described, and increased arterial stiffness was defined as PWV ≥ 12 m/s ,25.Twenty coronary segments were scored: each vessel was divided into three segments , except for the secondary branches of the right coronary artery (posterior ventricular and posterior descending), which were divided into proximal and distal segments. Stenosis higher than 50% in any coronary segment was graded 1 point and the sum of points for all 20 segments constituted the Extension Score. Lesion severity was calculated as follows: none and irregularities, 0 points; <50%, 0.3 points; 50–70%, 0.6 points; >70–90%, 0.8 points; and >90–100%, 0.95 points. The Severity Score was calculated through the sum of points for all 20 coronary segments .MYLIP rs9370867  polymorphism was detected by polymerase chain reaction (PCR) followed by high resolution melting (HRM) analysis with the Rotor Gene 6000® instrument  [Genomic DNA from subjects was extracted from peripheral blood following standard salting-out procedure. Genotypes for the  France) ,27. The  France) .2; 200 μM of each dNTP; 0.5 U Taq DNA Polymerase; 200 nM of each primer; 10 ng of genomic DNA template) with addition of fluorescent DNA-intercalating SYTO9® .Amplification of the fragment was performed using the primer sense 5’- TTGTGGACCTCGTTTCAAGA -3’ and antisense 5’- GCTGCAGTTCATGCTGCT -3’ (80 pairs base) for the rs9370867. A 40-cycle PCR was carried out with the following conditions: denaturation of the template DNA for first cycle of 94°C for 120 s, denaturation of 94°C for 20 s, annealing of 53.4°C for 20 s, and extension of 72°C for 22 s. PCR was performed using a 10 μL reactive solution  or type 2 diabetes mellitus were excluded. The subjects were classified as high-TC if their serum TC levels were ≥ 240 mg/dL and normal TC if their serum TC levels were < 240 mg/dL in the absence of lipid lowering medication. The subjects were also classified as combined hyperlipidemia if their serum TC and TG levels were ≥ 240 mg/dL and > 200 mg/dL, and as controls if TC and TG levels were < 240 mg/dL and < 150 mg/dL, respectively [The analysis stratified by hyperlipidemia was performed according to Weissglas-Volkov et al.‘s inclusion and exclusion criteria ,15. Fastectively ,15. All Table MYLIP polymorphism was found. Only hypertension frequency presented a trend (p = 0.05) in the general population  was higher in Whites (45.8% and 22.1%) compared with Blacks (15.2% and 3.1%) . In the patients submitted to coronary angiography, the frequencies of the MYLIP rs9370867 A variant allele and of the homozygous genotype (AA) was higher in Whites (44.6% and 20.7%) compared with Blacks (21.3% and 5.9%) . The genotypic distribution for the MYLIP rs9370867 polymorphism was in Hardy–Weinberg equilibrium according to ethnic groups.In both general population and patient samples, the ty Table . In the Table MYLIP rs9370867 genotypes with TC, LDL-C, HDL-C, triglycerides, and glycemia values in both samples  compared with subjects carrying AA genotypes  , even after adjustment for age, gender, and ethnicity  or with angiographic data  was observed Table .The analysis stratified by hyperlipidemia was performed according to Weissglas-Volkov et al.‘s inclusion and exclusion criteria (see Methods section for details) ,15. In tMYLIP rs9370867 polymorphism was associated with TC levels in a Mexican dyslipidemic sample and this genetic data was supported by functional data, which demonstrated that rs9370867 influences plasma cholesterol levels by modifying the degradation of the LDL-receptor [A recent study reported that receptor . In thisHere, the frequency of the A was much higher in Whites compared with Blacks. Previous studies reported that in African and Asian groups, the frequency is relatively low at 2% - 8%, whereas in European descent, the frequency is much higher at 49% - 60% ,29,30. TMYLIP studied polymorphism influences blood pressures.In the same way, this variation of the allele frequency among ethnicity influenced blood pressures data in general population samples. SBP, DBP, and MBP values were higher in GG genotype group (major frequency of Blacks) while lower values were observed in AA genotype group (minor frequency of Blacks). The adjustment for covariates plus ethnicity was not able to exclude the participation of the ethnicity variable in the observed results. But, in analysis stratified by ethnicity, this finding was not found in any ethnicity group. Corroborating with this observation, our group demonstrated in a recent study that SBP, DBP, and MBP values were higher in Black individuals than in the other ethnic groups in the Brazilian general population (p < 0.001) . Thus thMYLIP genetic loci contributing to variation in serum lipids [MYLIP region in Mexican individuals in order to restrict the associated region and identified the variant p.N342S (rs9370867). They associated this substitution with cholesterol levels in a Mexican dyslipidemic study sample [In this study, the replication of the previously identified association was not found in both general population and patient samples. Two GWAS of populations of European descent have identified m lipids ,13. Weisy sample .MYLIP functional polymorphisms could be differently distributed leading to distinct findings.It is important to report that the mentioned study have only observed the association in Mexican dyslipidemic individuals. Our Brazilian general population sample allowed a first assessment of this association in a general population and, our second sample, patients submitted to coronary angiography, allowed an analysis with major frequency of dyslipidemic individuals. In both samples, even after performing analysis according to Weissglas-Volkov et al.‘s criteria (see Methods section), no association was observed. The patterns of linkage disequilibrium vary across populations and ethnicities according to previous studies ,29,30; tMYLIP variant can present distinct results according to the studied population. In this moment, further studies are needed to reaffirm if the MYLIP p.N342S polymorphism is functional or not, and to identify other functional markers in this locus.Our findings indicate that association studies involving this The authors declare that they have no competing interests.PCJLS carried out the molecular genetic studies, statistical analysis and drafted the manuscript. TGMO carried out the molecular genetic studies. ACP participated in the design of the study, statistical analysis and manuscript preparation. ACP, PAL, JGM, JEK participated in the design of the study and were responsible for individual selection and characterization. All authors contributed critically to the manuscript, whose present version was read and approved by all.


A total of 103 AMI patients and 163 matched normal control samples were enrolled in the present study. The genomic DNA was extracted and subjected into polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. An association between the A homozygosity of the TNF-α-308G/A polymorphism and the onset of AMI was observed among the male subjects . An association between the T homozygosity of GNB3 C825T polymorphism and obesity was also observed . The TT genotype has a protective effect against acquiring AMI among the obese female population in Taiwan . In conclusion, TNF-α-308G/A and the GNB3 C825T polymorphisms are associated with obesity and AMI in the Taiwanese population.Acute myocardial infarction is a highly prevalent cardiovascular disease in Taiwan. Among several etiological risk factors, obesity and inflammation are strongly associated with the frequency of hypertension, cardiovascular disease, diabetes, and myocardial infarction. To discriminate obesity- and inflammation-related genes and the onset of acute myocardial infarction (AMI), a case-control study was conducted to investigate the association of the -308G/A polymorphisms of tumor necrosis factor (TNF)-α and the C825T polymorphism of guanidine nucleotide binding protein 3 (GNB3 Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. AMI has a high prevalence in Taiwanese cohorts, especially the elderly . Howeverp = 0.012; odds ratio = 3.0) [et al. demonstrated the higher frequency of the TNF-α-308AA+AG genotype among ST-elevation AMI patients compared with the non-ST-elevation AMI patients and normal individuals [Tumor necrosis factor-α (TNF-α), a key pro-inflammatory factor, has been linked to several human diseases. The -308G/A polymorphism in the promoter region of TNF-α is associated with its expression and effects, such as in lipid metabolism, insulin resistance, and endothelial function in cardiovascular disease [o = 3.0) . The asso = 3.0) . Antonicividuals .GNB3, T-homozygosity was found to be significantly more common among female myocardial infarction (MI) fatalities than the female control group . The investigators concluded that the C825T polymorphism may play a role in the development of MI, at least among females [GNB3 C825T polymorphism with arterial hypertension has been confirmed in smaller cohorts [GNB3 in terms of the onset of AMI among Taiwanese cohorts.G-proteins are essential partners of the seven transmembrane receptors for the activation or inhibition of intracellular signaling cascades. Most vasoactive or growth stimulating factors communicate via G proteins in virtually all cardiovascular tissues . Recentl females . The ass cohorts ,15. Some cohorts ,17. Seve cohorts . In the GNB3 C825T polymorphisms among the different subjects are shown in GNB3 C825T polymorphism was observed in the BMI ≥ 27 subgroup . However, no differences were observed in the genetic frequency distribution of the TNF-α-308G/A polymorphism when the AMI patients were compared with the normal subjects (group IIA).The genetic frequencies of the TNF-α-308G/A and the p = 0.032).The T allele carriage is beneficial for avoiding the onset of AMI among obese women in Taiwanese cohorts . The T homozygosity of the GNB3 C825T polymorphism results in a transcriptional truncated variant, and through the signal-enhancing ability of the G protein, it modulates adipogenesis and obesity risk. Furthermore, it is also associated with essential hypertension. However, a correlation between the T homozygote and the onset of AMI was not observed among Taiwanese cohorts, although a protective effect was observed within the obese female population. The results still need further confirmation via large-scale gene-associated studies within the Taiwanese cohorts. The controversial results might provide other clues as to whether this polymorphism does not directly affect the onset of AMI whether in males or females. The results might also modulate the AMI risk through the unknown mechanism, and this characteristic might differ among different ethnic groups.A high frequency of T allele carriage was also found among the AMI patients and the healthy control subjects. The T homozygosity acts as a predisposing factor for obesity . The G to A substitute of the -308 nucleotide located in the promoter region of the TNF-α gene would increase its mRNA transcription level and contribute to the elevation of serum TNF-α secretion. The increased pro-inflammatory cytokine may accelerate the formation of plaque rupture via the induction of unusual apoptosis activities of the cardiomyocytes, and modulates the AMI onset risk. Our finding was consistent with the current point of view. The male gender is considered a risk factor for the onset of AMI, but the exact genetic basis has not been investigated very well. The polymorphisms of inflammatory cytokines might probably be involved in this sex difference.For the TNF-α-308G/A polymorphism, we referred to the analyses that the association of gender might have an influence upon the AMI onset in advance because obesity might not be involved. An association between the A allele homozygosity of TNF-α-308G/A polymorphism with AMI within the male population was confirmed, but not in the female cohorts  Taiwanese patients with AMI recently registered in the Cardiovascular Disease Study from January 2006 to September 2006 in the Cardiology Division of Kaohsiung Armed Forces General Hospital or old AMI cases since March 1998 were recruited upon their return to the out-patient service of Kaoshiung Military General Hospital for their regular physical exams. Obesity was defined as having a BMI ≥ 27. Another group of 163  healthy individuals were recruited as the control subjects. Among the control subjects, 109 patients who have no history of AMI but have other cardiovascular symptoms were recruited as control group IIA (non-AMI subgroup), whereas 54 who have no conventional cardiovascular disease risk factors were designated as control group IIB . The conventional risk factors were described in a previous report [® Blood Genomic DNA kit . The A and G alleles at position -308 in the promoter region of the TNF-α gene were identified using the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) methodology as previously described, with minor modifications [GNB3 C825T polymorphism was determined by PCR-RFLP analysis. The primers used in the PCR were those described by Siffert et al. [BsaJI for 2–3 h at 37 °C. Thus, the BsaJI restriction site would be destroyed if the PCR product included a C to T substitution, whereas the C allele generated two fragments, 152 and 116 bp , and then stained with 0.5 μg/mL ethidium bromide solution, and visualized by Stratagene Eagle Eyes® II UV transilluminator . The gel image was recorded with a digital gel documentation system. To confirm the accuracy of genotyping by this method, we randomly selected 10% DNA samples and subjected them to direct DNA sequencing. In each instance, the genotype determined by the allele-specific PCR assay system or PCR-RFLP was identical to the samples determined by the confirmatory methods. The genotype of each polymorphism was confirmed by at least two well-trained laboratory technicians. To further confirm the PCR-RFLP results, directed DNA sequence analysis using forward and reverse primers was also performed  was collected from each subject into vacuum tubes containing 50 mmol/L ethylenediamine tetraacetic acid. Genomic DNA was isolated with a NucleoSpinications . A totalt et al. . The PCRd 116 bp . The amperformed .2 test, Fisher’s exact test, and Spearman’s correlation test to distinguish the significance of the variation among the subjects. Allele frequencies were estimated through the gene-counting method. The χ2 test was used to identify departure from the Hardy–Weinberg equilibrium. Each polymorphism was assessed according to dominant, recessive, and additive genetic models. The odds ratio and 95% confidence interval of each genotype conferring to AMI risk were also calculated. The statistical significance was defined as having a p value lower than 0.05, and all statistical methods were performed using the commercial statistical package software SPSS 13.0 for Windows .The experimental data on the gene polymorphisms were converted into categorical variables and compared with a χAMI is a polygenic illness, and its molecular genetic levels have been studied for quite some time. Many susceptible gene candidates have been confirmed to be highly associated with the onset and prognosis of AMI ,22. EvenIL-6 -174 G > C, have also been associated with acute coronary syndrome (ACS), resulting in higher risk of death among elderly ACS male patients [Growing evidence shows that inflammation plays a central role in the pathogenesis of AMI . Among tpatients . Polymorpatients ,31 . The homozygous T allele carriage of the GNB3 C825T is associated with obesity, but somehow has an opposite effect on the onset of AMI among our studied population.For the genetic variant of the rtension . As a rertension . However obesity ,32,33, a obesity ,34, myoc obesity , radial  obesity , and dia obesity . The widct on MI , or is act on MI . In addipatients . On the  in male . In thisGNB3 loci represents an ideal tool for preventive medicine, in that individuals at risk of obesity and AMI can be identified early and their genetic predisposition could be counteracted through changes in lifestyle. For individuals with borderline AMI, genotyping can facilitate decisions related to medical treatment as a positive test confirms an inherited form of AMI.Genotyping at the TNF-α and


There have been an increasing number of studies with evidence suggesting that the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genotypes may be implicated in the development of colorectal cancer (CRC) and colorectal adenoma (CRA). So far the published data on this association has remained controversial, however. We performed a meta-analysis of case-cohort and case-control studies using a subset of the published data, with an aim to derive a better understanding of the underlying relationship.A literature search was performed using Medline database for relevant studies published through October 31, 2011. A total of 39 publications were selected for this meta-analysis, including 11,724 cases and 16,215 controls for CRC, and 3,701 cases and 5,149 controls for CRA. In our pooled analysis of all these studies, the results of our meta-analysis suggested that the NAT1 genotype was not significantly associated with an elevated CRC risk . We also found that individuals with the rapid NAT2 genotype did have an elevated risk of CRC . There was no evidence for an association between the NAT1 and 2 rapid genotype and an elevated CRA risk .This meta-analysis suggests that individuals with NAT2 genotype had an elevated risk of CRC. There was no evidence for the association between NAT1 and 2 rapid genotype and CRA risk. Meat consumption has been linked to an increased risk of colorectal cancer (CRC) in many epidemiological studies So far, 36 NAT2 genetic variants have been identified in human, of which NAT2*4 is the most common allele associated with rapid acetylation Previous studies have investigated the relationship between the NAT1 and NAT2 genotype and predisposition to CRC and CRA Computerised searches in MEDLINE were performed using the following search terms “NAT1”, “NAT2”, “genotype”, and “colorectal cancer” or “colorectal adenoma” . As studies with the same population by different investigators or overlapping data by the same authors were found, the most recent or complete articles with the largest numbers of subjects were included. Abstracts written in non-English language were not considered. Our initial search and the process of study selection is summarised in All human-associated studies were included if they met the following criteria: (1) evaluate the association between NAT1 and NAT2 genotype and the risk of CRC and CRA; (2) CRC and CRA cases must have been diagnosed by histological examination; (3) studies with full-text article.Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist shown in . Of the Data were extracted from each study by two reviewers independently according to the prespecified selection criterias shown in . SupplemP value of more than the nominal level of 0.05 for the Q statistic indicated a lack of heterogeneity across studies, allowing the use of the fixed-effects model (the Mantel-Haenszel method). Subgroup analyses were performed by type of study, genotype (NAT1 and NAT2), ethnicity, and source of control. Funnel plot asymmetry was assessed by the method of Egger's linear regression test. The significance of the intercept was determined by the t test suggested by Egger .Statistical analyses were done with Stata, version 11.0. Heterogeneity among studies was checked by the random-effects model (the DerSimonian and Laird method) if there was significant heterogeneity. A As summarised in P = 0.31, 2I = 13.5%). In the subgroup analyses by ethnicity, no significant associations were found in all comparisons .P = 0.06, 2I = 29.3%).Based on meta-analysis from 34 studies, a significant increased risk of colorectal cancer was observed for those individuals with rapid acetylator polymorphisms in NAT2 . When stratified by ethnicity, elevated risk of CRC was also observed among Caucasian populations . There was no evidence for the association between the rapid genotype and CRC risk in Asian and African. And in a stratified analysis by source of control, individuals carrying the NAT2 rapid genotype were not significantly associated with increased CRC risk. There was no statistically heterogeneity among these studies in overall comparisons . Although the sample size for cases and controls in 39 publications ranged from 66 to 1,963, the corresponding pooled ORs were not qualitatively altered with or without the study of small sample.We performed Begg's funnel plot and Egger's test to assess the publication bias of literatures. As shown in Allelic polymorphism of the NAT2 enzyme has been studied for a long time, first detected phenotypically, based on enzyme activity distribution in healthy subjects, and later these activity differences were bound to an allelic polymorphism Variations in the frequency of NAT1 and NAT2 genotype among different ethnic groups have been reported. Our results showed that frequency of the NAT1 rapid acetylation phenotype was 65.4% in Asian populations, which was significantly higher than that in European populations (35.8%). And for NAT2 phenotype, the rapid acetylation phenotype frequency was 79.8% in Asians and 42.4% in Europeans. In the stratified analysis by ethnicity, elevated risk was found for Caucasian. But there was no evidence for the association between NAT1 and NAT2 genotype and CRC risk among Asian populations.There is epidemiologic evidence for differential effects of acetylation with CRA risk by ethnicity. For example, Probst-Hensch et al. reported an inverse association between NAT2 rapid genotypes and colorectal adenomas among African Americans, but an increased risk among whites Several studies have also investigated the association between NAT1 and NAT2 genotypes and CRC risk, as reviewed in 2000 The present study has several limitations that need consideration. First, we only considered two metabolic enzymes (NAT1 and NAT2). Because additional enzymes are involved in the bioactivation and detoxification of heterocyclic amine, they may also play a role in modifying CRC or CRA risk, this may increase the misclassification of measured variables. Second, only three studies evaluated associations between NAT1 or NAT2 genotype and CRC risk in histologic subgroup, such as associations among cases in the Duke stage In conclusion, our meta-analysis suggests that individuals with the rapid NAT2 genotype had elevated risk of CRC. There was no evidence for the association between NAT1 and 2 rapid genotype and CRA risk. Our study significantly increased the statistical power of the analysis based on the studies for CRC and CRA risk. Further studies on estimating the effect of gene-gene and gene-environment interactions may eventually lead to a better and more comprehensive understanding of the association between the NAT1 and NAT2 genotype and CRC and CRA risk.


SELE gene and CAD risk were investigated broadly, but the results were inconsistent. In the present study, we performed a meta-analysis to systematically evaluate the associations between the two polymorphisms and the risk of CAD.E-selectin (SELE) mediates the rolling and adhesion of leukocytes on activated endothelial cells and plays a critial role in the pathogenesis of coronary artery disease (CAD). Associatons between the A561C and G98T polymorphisms of the 2Ι. Meta-regression was used to explore the potential sources of between-study heterogeneity. Peters's linear regression test was used to estimate the publication bias.Comprehensive research was conducted to identify relevant studies. The fixed or random effect model was selected based on the heterogeneity among studies, which was evaluated with Q-test and Overall, 24 articles involving 3694 cases and 3469 controls were included. After excluding articles deviating from Hardy–Weinberg equilibrium in controls and sensitive analysis, our meta-analysis showed a significant association between the A561C ploymprphism and CAD in dominant  and codominant  models. As for the G98T polymorphism, significantly increased CAD risk was observed in dominant  and codominant  models, but after subgroup analysis, the association was not significant among Caucasians in dominant  and codominant  models.SELE gene polymorphisms  were significantly associated with increased risk of CAD. However, after subgroup analysis no significant association was found among Caucasians for the G98T polymorphism, which may be due to the small sample size and other confounding factors. Future investigations with multicenter, large-scale, and multi-ethnic groups are needed.Despite some limitations, our meta-analysis suggested that the  Coronary artery disease (CAD) has become a major cause of death and disability, accounting for up to 40% of all lethal events Inflammation plays a major role in pathogenesis of atherosclerosis http://www.ncbi.nlm.nih.gov/gene/6401), consisting of 14 exons and 13 introns spanning about 13 kilobases of DNA. Several polymorphisms of the SELE gene have been mentioned, the following two polymorphisms were considered the most interesting, (1) the A561C polymorphism (rs5361) E-selectin , is a surface glycoprotein molecule expressed on endothelial cells upon activation by cytokines SELE gene A561C and G98T polymorphisms might be associated with a predisposition to severe coronary or peripheral atherosclerosis  SELE gene polymorphisms (A561C and G98T) on the risk of CAD; (2) evaluate the potential heterogeneity among studies; and (3) explore the potential publication bias.Previously it was suggested that the A computer-based online retrieval was performed using the databases of PubMed, Web of Knowledge (ISI), China National Knowledge Infrastructure (CNKI), China Biology Medical literature database (CBM), Database of Chinese Scientific and Technical Periodicals (VIP) and Google Scholar covering the period from 1994 to August 2012. The following Medical Subject Headings (MeSH) were used as the search terms: “Cardiovascular Diseases”, “E-selectin”, and “Genetic Variation”. The folllowing keywords were also used in the search: “coronary artery disease”, “coronary heart disease”, “myocardial infarction”, “angina pectoris”, “ischemic heart disease”, “coronary death” and “E-selectin”, “SELE”, “CD62E”, “ELAM1” and “polymorphism”, “mut*”, “varia*”. We further checked the reference lists of the relevant papers we identified, including reviews and meta-analysis, to discover other relevant studies that were not captured initially, and contacted the authors of published papers directly, if crucial data was not reported in the original papers. We restricted search results to papers published in English or Chinese.SELE gene and susceptibility to CAD; (2) sufficient genotype data in case and control groups in a case–control study or exposed and unexposed groups in a cohort study was provided or can be calculated; (3) subjects of each study group should come from the same time period and ethnicity; (4) If there were multiple publications from the same study group, the most recent or complete study with the largest sample size was used; (5) The diagnosis of CAD was definite, and relevant outcomes in cases should be confirmed based on WHO criteria or coronary arteriography .Studies included in our meta-analysis had to be in accordance with the following criteria: (1) case-control or cohort study published in an original study aimed to explore the associations of the A561C and/or G98T in the All studies were reviewed by two investigators independently to identify the eligible studies included in this meta-analysis. In case of disagreement, consensus was obtained with a third reviewer by joint review of the study.Study eligibility was determined based on the selection criteria, and data was entered into a preformatted spreadsheet by two independent investigators who reached a consensus on all of the items. Data extracted from eligible studies were as follows: the first author, year of publication, country, ethnic origin, numbers of case (exposed) and control (unexposed) groups, genotype and allele distributions, the variant allele frequency in control (unexposed) groups, mean age, male percentage in case (exposed) and control (unexposed) groups. For studies including subjects from different types of populations, data was extracted separately from each population.SELE gene in controls with the significance set at P<0.05. The inverse-variance weighted mean of the logarithm of Odds Ratio (OR) with 95% confidence intervals (CI) was calculated to assess the strength of the associations between the SELE gene A561C, G98T polymorphisms and risk of CAD. The pooled ORs were calculated by using the dominant model  and the codominant model . Between-study heterogeneity was calculated by the Chi-square-based Q-test and considered significant if P<0.05 2Ι of Higgins and Thompson 2Ι measures the percentage of variability in point estimates that is due to heterogeneity rather than sampling error or chance. If substantial heterogeneity (heterogeneityP <0.05) was observed among the studies, the DerSimonian and Laird random effect model (REM) was used to estimate the pooled OR. Otherwise, the Mantel–Haenszel fixed effect model (FEM) was adopted. Meta-regression with restricted maximum likelihood estimation P<0.05 was accepted as statistically significant.Chi-squared analysis with exact probability was used to assess deviation from the Hardy-Weinberg equilibrium (HWE) for the A561C and G98T genotype distributions of the The initial search yielded 386 potentially eligible papers based on the above search criteria, 329 papers were excluded after title or abstract review, and 33 additonal papers were excluded due to duplicate studies, reviews, studies with insufficient information and so on. Finally, 24 The included papers were all case-control studies involving 3694 cases and 3469 controls. Among the 24 papers involving 32 outcomes, 21 papers involving 23 outcomes were for the A561C polymorphism and 8 papers involving 9 outcomes were for the G98T polymorphism. In most of the studies the polymorphisms in the controls were found to occur in frequencies consistent with HWE, with the exception of one article As shown in SELE gene G98T polymorphism.As summarized in SELE gene A561C polymorphism after excluding articles deviating from HWE in controls and the sensitive analysis.For the A561C polymorphism, after exclusion of the article that deviated from HWE in controls and the sensitive analysis, the C allele associated with CAD remained significant in dominant  and codominant  models. After the subgroup analysis, the associations were not altered substantially. heterogeneityP <0.05) among studies was demonstrated in dominant and codominant models considering the association of the A561C polymorphism with CAD after exclusion of articles deviating from HWE in controls. In order to systematically assess the heterogeneity among the studies, univariate meta-regression was conducted to explore the potential sources. Among the covariates of ethnicity, publication year, sex, and age for the A561C polymorphism, no covariates had a significant impact on the between-study heterogeneity with the P value of the above covariates being 0.05, 0.90, 0.41 and 0.78 separately in the dominant model. No significant between-study heterogeneity was found in the above-mentioned inherited models considering the association of the G98T polymorphism with CAD.Strong evidence of heterogeneity  was found, with similar results for the G98T polymorphism , indicating low publication bias in the current meta-analysis.Peters's linear regression test was performed to estimate the publication bias of the literature. For the A561C polymorphism, after exclusion of articles deviating from HWE in controls and the sensitive analysis, no statistically significant difference  among studies was demonstrated in the dominant and codominant models, and we then performed an univariate meta-regression to explore the potential sources, including ethnicity, publication year, sex, and age, we found that no covariates above had a significant impact on the between-study heterogeneity. However, as we all know, CAD has a complex aetiology and pathophysiology generated by the combined effects of genes and environmental factors. Numerous genetic and environmental variables, as well as their interaction, may be potential contributors to this disease-effect unconformity. Besides an indeterminate number of characteristics that vary among studies, confounding factors could further contribute to between-study heterogeneity.In our meta-analysis, a total of 3518 cases and 3317 controls from 23 populations were included, however most of the populations were Asian . A significant association was found between the C allele and CAD risk in the dominant and codominant models. After subgroup analysis by ethnicity, the assosiation was also significant in Asian and Caucasian populations. Strong evidence of heterogeneity (http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=5361) and our present study, which shows that the distribution of the C allele frequency in controls was 0.04 and 0.09 in Asian and Caucasian populations separately, the C allele frequency in the Asian populations is significantly lower than that in the Caucasian populations. Considering that the different genetic background may contribute to the between-study heterogeneity, we performed subgroup analysis by ethinicity categorised as Asian and Caucasian, though in our present meta-analysis ethnicity was not found to be responsible for the between-study heterogeneity.According to the SNP database at the NIH Click here for additional data file.


E-selectin Ser128Arg polymorphism and the P-selectin Thr715Pro polymorphism have been investigated widely but with inconsistent results. We performed a comprehensive meta-analysis to shed light on this issue.The selectins play important roles in the inflammatory process of coronary artery disease (CAD) and myocardial infarction (MI). Previous studies have shown ambiguous findings regarding a possible association between the selectin genes and CAD. The Data were extracted by searches of MEDLINE, Embase, CNKI, Wanfang, Google Scholar, PORTA, GeNii, CiNii, J-STAGE, Nurimedia and Koreanstudies Information Service System [Kiss] up to October 2013, in which 10 studies on the Ser128Arg polymorphism with 3369 cases and 2577 controls and 10 studies on the Thr715Pro polymorphism with 5886 cases and 18345 controls. A random-effects model was used to calculate the combined odds ratios. The between-study heterogeneity and publication bias were addressed.heterogeneity = 0.01); The 715Pro conferred a non-significant risk reduction relative to the 715Thr .Subgroup analyses demonstrated that the 128Arg carriers had a significant increased risk of CAD among Asians  but not among Caucasians . Carrier status for the 715Pro was significantly associated with reduced risk of MI . The asymmetric funnel plot and the Egger's test (P = 0.041) suggested the presence of publication bias for the Ser128Arg polymorphism.The 128Arg carriers had a significant increased risk of CAD (allele comparison: P = 0.02, OR = 1.33, 95%CI 1.04–1.69, POur results suggested there is an increase in the risk of CAD conferred by the Ser128Arg polymorphism and the thr715Pro polymorphism may be a protective factor of MI. It has been known for years that coronary artery disease (CAD) and myocardial infarction (MI) are the main killers in the world. The pathogenesis of CAD and MI involves important inflammatory components P-selectin gene is associated with the susceptibility to CAD and MI. These two polymorphisms were the most investigated, but with conflicting results. It should be considered that the sample size in the previous studies was relatively small. Hence, the studies had low statistical power to detect modest associations of genotype with CAD. To shed some light on this divergence and maximize statistical power, we sought to evaluate the correlation of these two polymorphisms of the selectin genes with CAD by performing a comprehensive meta-analysis of available individual studies. Furthermore, the between-study heterogeneity and the publication bias were addressed.Although the in vivo study has suggested that E-selectin and P-selectin exert similar effects of leukocyte adhesion on atherosclerosis lesions. The exact roles of E-selectin and P-selectin remain unclear. Estimates have placed genetic predisposition to be responsible for 40–60% of susceptibility to CAD We followed the guidelines of the 2009 preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement All the studies conformed to the following criteria were potentially involved: (1) Studies followed case-control or cross-sectional design (studies without controls were excluded); (3) Studies providing adequate allele or genotype information on the examined polymorphisms; (4) Studies published in English journals or their supplements; (5) If multiple studies derived from a common population, only the study with the largest sample size was extracted to avoid overlapping data; (6) The genotype frequency amongst control must conform to Hardy-Weinberg equilibrium (HWE).Standard definitions were used to diagnosis disease outcomes Two authors (Z.W. and Y.Lou.) independently extracted the relevant information from qualified studies by the standard data-collection protocol according to the inclusion criteria. The data were entered into separate databases in duplicate by the two authors. Any encountered inconsistencies were resolved at a consensus meeting. The following data was gathered based on different cohort: first author's name, publication year, ethnicity, geographic location, study design, population source, disease outcomes, matching variables, clinical characteristics , the distribution of the Ser128Arg and Thr715Pro genotype in both patients and controls and conformity to genotype frequencies with HWE. Continuous variables were manifested as mean ± standard deviation (SD) or median (5th and 95th percentiles).2 statistic. A significant Q statistic test (P<0.10) indicated heterogeneity among studies. I2 = 100%×(Q−df)/Q, measures the proportion of the between-study variability due to heterogeneity rather than chancehttp://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl).Data management and processing were performed using Review Manager software release 5.0  and Stata 11.0 . The combined odd ratios (ORs) corresponding to 95% confidence intervals (CIs) were calculated under the random-effects model using DerSimonian & Laird method. Considering the relatively low number of homozygote genotype, we only estimate the effect size of these two polymorphisms on CAD under the allelic and dominant models. The possibility of heterogeneity was assessed using Cochran's chi-square based Q statistic test A univariate meta-regression was used to explore potential factors associated with the genetic heterogeneity. A cumulative meta-analysis might indicate the influence of the initial published research on subsequent studies and the evolution of the combined estimates with ascending date of publication. A sensitivity analysis was conducted using one-study removal approach to identify the influence of each study on the overall effect size E-selectin Ser128Arg polymorphism and 9 of the P-selectin Thr715Pro polymorphism) with adequate information satisfied our inclusion criteria. The study by Morgan et al.et al.et al.A total of 395 relevant citations were reviewed based on our selection strategy. The stepwise selection process is shown in E-selectin Ser128Arg polymorphism and 10 studies with 5,886 cases and 18,345 controls for the P-selectin Thr715Pro polymorphism involved in our meta-analysis. The clinical characteristics of included studies are shown in HWE>0.05).There were 10 studies with 3,369 CAD patients and 2,577 controls for the E-selecitn 128Arg allele was 8.7% in cases and 7.7% in controls. The frequency of the 128Arg allele among Caucasians (9.0% cases & 9.0% controls) was moderately higher than that among Asians (6.5% cases & 3.3% controls). As for the P-selectin Thr715Pro polymorphism, most of the qualified studies were performed among Caucasians except one study  with remarkable heterogeneity and dominant model  .E-selectin Ser128Arg polymorphism and CAD in total analysis. As for the P-selectin Thr715Pro polymorphism, the study by Herrmann et al.heterogeneity  = 0.21) after removing this study and the effect size did not change materially.Sensitivity analyses demonstrated that no single study influenced the heterogeneity and ORs when evaluating the association between the Cumulative trends for allelic contrast of these two polymorphisms suggested there was not any distinct evidence for the first published study that triggered the ensuing replication of other studies that tried to replicate this initial result (data not shown).The funnel plot for the Ser128Arg polymorphism was distinct asymmetric for small negative studies. The Egger's (P = 0.041) and the Begg-Mazumdar (P = 0.016) test suggested a presence of publication bias. By using the trim and fill method, we found that if the publication bias was the sole source of the funnel plot asymmetry, 3 studies were needed to be symmetrical . For theheterogeneity = 0.77) but not among Caucasians  ; The 128Arg allele carriers had a marginal risk increase (42%) of CAD in matched studies under the dominant model . Data were then stratified according to publication year. The out points of the publication year (2007 for the E-selectin Ser128Arg polymorphism & 2005 for the P-selectin Thr715Pro polymorphism) were chosen as the median. Risk increase in the studies published before 2007  was significantly different from that in the studies published in/after 2007  ; When da = 0.18) .P-selectin Thr715Pro polymorphism, the 715Pro carriers had a significant 19% risk reduction in MI group  and a suggestive risk effect in CAD group  . However, there is a lack of dramatic association of the Thr715Pro polymorphism with CAD risk when data were categorized according to study design (prospective/retrospective), population source (P-B/H-B) and publication date (<2005/≥2005)(As for the  = 0.26) . In addi05/≥2005).E-selectin Ser128Arg polymorphism and the P-selectin Thr715Pro polymorphism.A univariate meta-regression analysis was used to detect the effect of potential factors on genetic heterogeneity. Single covariates such as ethnicity, population source, case definition, study design, matching information, language, publication year and the baseline characteristics of total population were added in a series of univariate models. There was no evidence suggesting these factors were responsible for the between-study heterogeneity for both the E-selectin 128Arg allele was significant associated with an increase of 33% in CAD risk with remarkable heterogeneity. We hypothesized the ethnicity may be a potential origin of between-study heterogeneity. The subgroup analysis suggested that the risk increase of the Ser128Arg polymorphism on CAD among Asians were dramatically larger than Caucasians. Although the minor allele frequency of the Ser128Arg polymorphism was slightly different between Asians and Caucasians, this inconsistence can be attributed to the pleiotropic effect of the Ser128Arg polymorphism due to various genetic ancestral backgrounds. Different linkage disequilibrium patterns due to different populations were likely to be another explanation. A SNP may be in close linkage with another nearby causal variant in one ethnic population but not in another. Ethnicity might be a source of between-study heterogeneity for the Ser128Arg polymorphism. However, we were unable to evaluate the influence of ethnicity on the CAD risk of the P-selectin 715Pro carriers, because most of the eligible studies concerning the Thr715Pro polymorphism were conducted among Caucasians. It is difficult to estimate the modest association in other racial descents unless examining a larger population. Constructing optimized databases and replicating the results of these two polymorphisms related to CAD in different populations may benefit to draw definitive conclusions.There has been growing interest in the role of cellular adhesion molecules in atherosclerosis. Among these, the selectins play essential roles in the first step in leukocyte recruitment and infiltration, which is vital in the key process of atherosclerosisx antigen (sLex) is regarded as the preliminary step of endothelial activation, damage or turnover and serves as a molecular marker for atherosclerosis P-selectin Thr715Pro polymorphism exhibited as a significant protect factor of MI but not CAD. It is could be a likely explanation if the protective effect of the 715Pro allele was directed against thrombosis rather than atherosclerosisAs well as the obvious impact of ethnicity, distinct heterogeneity can be observed when comparing different disease types . Although both CAD and MI most commonly result from atherosclerotic occlusion of the coronary arteries and share many of the same inflammatory factors, the pathological manifestations of CAD and MI are quite different. Acute atherosclerotic plaque disruption with thrombosis, which compromises coronary blood flow, is the key process of MIE-selectin Ser128Arg polymorphism in the meta-analysis. This is said to occur when the chance of the publication of a smaller study increases if it shows a stronger effect Our study still has several limitations. First, only two of the most common SNPs of the selectin genes were investigated. We could not rule out the possible influence of other rare variations or uncommon SNPs that have not been extensively studied. Considering the effect of a SNP on a multi-factorial disease such as CAD is relatively weak, particular haplotypes involving the Ser128Arg polymorphism or another functional mutation in linkage disequilibrium may have more significance. Another problem should be cautiously considered. There was evidence for the publication bias of the E-selectin Ser128Arg polymorphism was associated with an increased risk of CAD while the P-selectin Thr715Pro polymorphism could be a protective factor of MI. We suggested that the members of selectin family appear to play heterogeneous roles at the development of atherosclerosis and therefore be new candidate targets for diagnostic purposes and therapeutic interventions in atherosclerosis.In summary, our meta-analysis expanded previous individual studies by supporting the evidence that the Checklist S1The PRISMA checklist for this meta-analysis.(DOC)Click here for additional data file.


There has been a long-standing debate on the complex correlation between the development of human hand preference and brain lateralization. Handedness, used as a proxy for cerebral lateralization, is a topic of considerable importance because of its potential to reveal the mechanisms of the underlying pathophysiology of problems related to brain development or cognitive systems. Twin studies, which represent an important method of research in human genetics, would provide valuable suggestions to the studies on the relationship between lateralization and cognitive systems. Many studies have been performed using twin subjects; however, the results are inconsistent, partly because of sample size, background assumptions, data limits or inaccuracies, incorrect zygosity classification, and/or lack of birth histories. In summary, within the long history and large number of twin studies performed on handedness, a surprisingly large number of controversial findings have been reported, suggesting the complicated nature of this phenotype. In this mini review, the wide variety of twin studies on human handedness performed to date are introduced. Approximately 90% of humans are right-handed, with the rest made up of left-handed and ambidextrous individuals. It is well established as to singletons that the prevalence of left-handedness in males is slightly higher than that in females . There hThis Mini Review summarizes the twin studies of human handedness laterality, and touches on the relevant research factors such as twin type, chorion and placentation types, zygosity, gender effects, birth-order effects, handedness discordance, and brain measures using magnetic resonance imaging (MRI) and functional MRI (fMRI). Genetic twin analyses of the origins of handedness were not included. The relationship between handedness and disease is omitted here, as it is beyond the scope of this brief review. Other human laterality, such as footedness, is also excluded because of an insufficient number of twin studies to date.There are two types of twins, and these types have completely different origins. Monozygotic (MZ) twins derive from the division of a single zygote, whereas dizygotic (DZ) twins derive from the independent release and subsequent fertilization of two ova . HandednIt is commonly assumed that separation takes place in the early days of multicellular embryo development rather than at the initial zygote stage. If this split occurs within the first 72 h, the result is dichorionic monozygotic (DC-MZ) twin pregnancy. If the split takes place from 3 to 12 days after fertilization, a monochorionic monozygotic (MC-MZ) twin pregnancy is produced . Twin-twMZ twin pairs share 100% of their DNA sequence, which means that most variation in pairs’ traits is due to their unique or shared environment. DZ twin pairs share about 50% of their polymorphisms. DZ twin pairs are helpful to study because they tend to share many aspects of their environment by virtue of being born in the same time and place. Twin studies help disentangle the relative importance of environmental and genetic influences on individual traits and behaviors by comparing the similarity of MZ and DZ twin pairs, although they may differ due to fetal development and birth histories. For example, large birth weight differences in TTTS may indicate neurological risk in the smaller twin.Many studies  suggesteAccording to Twins are more likely than singletons to be born prematurely and/or to experience perinatal injuries, and it has been suggested that the increase in left-handedness in neurologically intact twins reflects one end of the spectrum of the pathological left-handedness syndrome as formulated by Ever since In a sample of 44 pairs of MZ twin children, consisting of 23 MC-MZ and 21 DC-MZ selected from hospital records, 18% of MC-MZ pairs were discordant pairs, and 26% of DC-MZ pairs were discordant . CarlierReviews of the literature examining handedness in twins by If perinatal complication is related to left-handedness, the prevalence of left-handedness in MZ should be higher than that in DZ, because MZ, especially MC-MZ, biologically have more birth complications . With imAccording to the review by per se that contributes to an excess of left-handedness in twins. According to the meta-analysis of According to In contrast to the Geschwind–Behan–Galaburda hypothesis, an alternative theory suggests that left-handedness is caused by decreased levels of testosterone . This caThree studies  have dirThere are different risks to being first and to being second born within twin pairs – both carry risks. The first born has to prepare the birth canal, the second born, if larger and with a significant delay – may be at higher risk of anoxia – for vaginal deliveries. In a random sample of 104 pairs of handedness-discordant twins of 6 years of age or older, a significant relationship has been found between birth order and handedness in MZ twins, there being an excess of left-handed individuals among first-born twins. No such relation has been found in DZ twins . On the MZ twin pairs with discordant handedness are as genotypically alike as it is possible to be, and it is therefore possible to study the consequences of phenotypical left or mixed handedness with the ideal set of controls: namely, the right-handed twin members.Several researchers used handedness as a marker of intrauterine neurological development and compared the handedness and brain asymmetry using fMRI. MZ twin pairs are often examined as an initial step toward documenting the nature of laterality. The report of It is often said that twin study represents a way of doing experimental research in a natural setting. Many studies have been performed using twin subjects; however, the results are inconsistent, partly because of the small sample size used or faulty assumptions in theoretical models cf. . NeverthWhile twin study may not provide conclusive evidence as to the origins or mechanisms between human handedness and brain development or cognitive process, it indubitably provides an important first step to clarify these problems. It is essential however that neurodevelopmental factors specific to twinnedness be included in the analysis cf. .The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The Alberta oil sands are an important economic resource in Canada, but there is growing concern over the environmental and health effects as a result of contaminant releases and exposures. Recent studies have shown a temporal and spatial trend of increased polycyclic aromatic hydrocarbon (PAH) concentrations in sediments and snowpack near the Athabasca oil sands operations , but thus far similar studies have not been done for the Cold Lake region where steam assisted gravity drainage (in situ) extraction is performed.Many PAHs are known mutagenic carcinogens, and this study measured soil and atmospheric concentrations of PAHs in the Cold Lake region to assess the excess lifetime cancer risk posed to the First Nations’ inhabitants of the region. Using both deterministic and probabilistic risk assessment methods, excess lifetime cancer risks were calculated for exposures from inhalation or inadvertent soil ingestion.The mean excess cancer risk for First Nations’ people through ingestion who engage in traditional wilderness activities in the Cold Lake region was 0.02 new cases per 100,000 with an upper 95% risk level of 0.07 cases per 100,000. Exposure to PAHs via inhalation revealed a maximum excess lifetime cancer risk of less than 0.1 cases per 100,000.Excess lifetime risk values below 1 case per 100,000 is generally considered negligible, thus our analyses did not demonstrate any significant increases in cancer risks associated with PAH exposures for First Nations people inhabiting the Cold Lake region. Canada has the third largest proven oil reserves in the world . The oilin-situ thermal heavy oil (bitumen) extraction operation in the world, producing 54,600 barrels of bitumen each day. Currently, in-situ bitumen extraction accounts for 47% of oil sands extraction in Alberta, and will soon become the dominant form of oil sands extraction, overtaking open pit mining pyrene; BW: Body weight; CCME: Canadian Council of Ministers of the Environment; CF: Conversion factor; CS: Concentration; CSF: Cancer slope factor; ED: Exposure duration; EF: Exposure frequency; GFF: Glass fibre filter; HHRA: Human health risk assessment; IR: Intake rate; PAH: Polycyclic aromatic hydrocarbon; PEF: Potency equivalency factors; PDF: Probability density functions; PUF: Polyurethane foam cartridge; SD: Standard deviation.The authors have no conflict of interest to declare.GI carried out the collection of soil and atmospheric samples, processed all samples, performed the data analyses, and prepared a draft of the manuscript. JMB conceived of the study, participated in its design, and helped draft the manuscript. JRD participated in study design, data analysis, and helped draft the manuscript. LEK participated in study design, method development and data analysis. PAW participated in study design, data analysis, and helped draft the manuscript. All authors have read and approved the final manuscript.13C labeled PAHs, and MDL is the calculated method detection limit.PAH method detection limit and calculation for soil samples. Ce is analyte concentration, Ve, is injection analyte volume, Vs is average sample mass measured, R% is the average recovery rate of Click here for fileList of the 16 priority PAHs measured for this study and their Potency Equivalency Factors .Click here for file13C labeled PAHs, and MDL is the calculated method detection limit.Method detection limit and calculation for particulate PAH samples measured on GFFs. Ce is analyte concentration, Ve, is injection analyte volume, Vs is average sample mass measured, R% is the average recovery rate of Click here for file13C labeled PAHs, and MDL is the calculated method detection limit.Method detection limit and calculation for gaseous PAH samples measured on PUF cartridges. Ce is analyte concentration, Ve, is injection analyte volume, Vs is average sample mass measured, R% is the average recovery rate of Click here for file