Endothelial nitric oxide synthase 894 G > T polymorphism and thrombotic disease: A Meta-Analysis of 17 studies involving 8808 subjects

Introduction

Endothelial nitric oxide synthase (eNOS) 894 G > T polymorphism may influence the risk of thrombotic disease, but data from published studies with low statistical power are inconclusive. To investigate the association between the gene polymorphism and thrombotic disease, a meta-analysis was performed.

Materials and Methods

Case–control studies evaluating the association between the eNOS G894T polymorphism, Glu298Asp and thrombotic disease were searched in PubMed, OVID, Web of Science, Google Scholar and China Biology Medicine disc (CBM). Data were available for 4742 cases and 4066 controls from 17 studies.

Results

In all, although there was a significant association between G894T and thrombotic disease (G/T + T/T vs. G/G: OR = 1.364, 95%CI = 1.126-1.652, P = 0.001; T/T vs. G/T + G/G: OR = 1.861, 95%CI = 1.207-2.870, P = 0.005; TT vs. GG: OR = 1.938, 95%CI = 1.244-3.021, P = 0.003; G/T vs. G/G: OR = 1.225, 95%CI = 1.022-1.469, P = 0.028), there was significant heterogeneity among studies (P* < 0.001). In subgroup analysis, there was significant association with no heterogeneity in venous thrombosis (G/T + T/T vs. G/G: OR = 1.409, 95%CI = 1.135-1.750, P = 0.002, P* = 0.508; T/T vs. G/G: OR = 1.640, 95%CI = 1.011-2.660, P = 0.045, P* = 0.333; G/T vs. G/G: OR = 1.357, 95%CI = 1.082-1.701, P = 0.008, P* = 0.595) and in Asian population (G/T + T/T vs. G/G: OR = 1.722, 95%CI = 1.443-2.055, P < 0.001, P* = 0.541; T/T vs. G/T + G/G: OR = 2.357, 95%CI = 1.389-4.000, P = 0.001, P* = 0.908; T/T vs. G/G: OR = 2.813, 95%CI = 1.645-4.810, P < 0.001, P* = 0.969; G/T vs. G/G: OR = 1.645, 95%CI = 1.370-1.975, P < 0.001, P* = 0.489).

Conclusions

Findings of this meta-analysis demonstrated that eNOS G894T polymorphism may be a risk factor for venous thrombosis, and in Asia the polymorphism may increase the risk of developing thrombotic disease.     

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of venous thromboembolism in Chinese population

Introduction

Endothelium derived nitric oxide (NO) is a key mediator of vascular homeostasis. Endothelial nitric oxide synthase (eNOS) gene, by affecting the expression and functional activity of the eNOS enzyme, thereby reducing NO availability, may be implicated in venous thromboembolism (VTE). We investigated the eNOS G894T polymorphism in VTE patients in the Chinese population.

Materials and methods

A case-control study was conducted in a general hospital. Blood samples, collected from 462 consecutive patients with VTE and 462 healthy controls, were used for DNA extraction. Single nucleotide polymorphisms (SNP) of eNOS (894 G/T) were determined by allele specific-polymerase chain reaction (ARMS-PCR) analysis.

Results

The eNOS 894 G/T polymorphism alleles distribution was in agreement with the principle of Hardy-Weinberg equilibrium. The prevalence of homozygote, heterozygote and pathological homozygote for the eNOS G894T polymorphism in VTE patients was 79.7%, 18.1% and 2.2%, respectively (controls: 86.6%,12.3% and 1.1%). T allele distribution in the VTE (11.3%) and especially the male VTE patients (12.5%) was more common than in healthy controls (7.3%). The frequency of GT + TT genotype was significantly higher among the age ≤ 55 years patients in VTE group than in controls (20.1% vs. 12.2%, P = 0.033).

Conclusion

Our result demonstrates that the 894 G/T polymorphism variant of eNOS is a risk factor for VTE in Chinese population.     

Influence of the β-fibrinogen-455G/A polymorphism on development of ischemic stroke and coronary heart disease

Background

Ischemic stroke (IS) and coronary heart disease (CHD) are two vascular disorders that are a common cause of death worldwide. Several studies have assessed the association of the β-fibrinogen-455G/A (FGB-455G/A) polymorphism and risk of IS and CHD, but the results are still inconsistent. Our study aimed to investigate whether the FGB-455G/A polymorphism was associated with susceptibility to IS and CHD by using meta-analysis.

Methods

Relevant studies were identified from PubMed, Embase and four Chinese database up to July 2013.Data were analyzed and processed by Stata 11.2. A pooled OR with 95% CI was calculated to estimate the strength of the genetic association. Cumulative meta-analysis was performed to assess the tendency of pooled OR over time.

Results

45 studies based on a total of 7238 cases and 7395 controls were included in our meta-analysis. The results indicated that the FGB-455G/A polymorphism is associated with the risk of IS when compared with the dominant model (OR = 1.518, 95%CI = 1.279-1.802 for AA + GA vs. GG). In the subgroup analysis by ethnicity, significantly elevated risks were associated with the A allele in Asians (OR = 1.700, 95%CI = 1.417-2.040), but not in Caucasians (OR = 0.942, 95%CI = 0.813-1.091). Both the hypertension and non-hypertension subgroups reached significant results, but no significance was found when stratified according to sex or subtype of IS. Results indicate that the FGB-455G/A polymorphism is associated with CHD (OR = 1.802, 95%CI = 1.445-2.246).

Conclusion

Our meta-analysis suggests that the FGB-455G/A polymorphism contributes to susceptibility to IS and CHD.     

Lack of evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke: A meta-analysis of 8,800 subjects

Introduction

Epidemiological studies have evaluated the association between factor XIII-A (FXIII-A) Val34Leu polymorphism and risk of ischemic stroke, but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies.

Methods

Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation (using the Newcastle-Ottawa Scale, NOS) were independently conducted in duplicate. Statistical analyses were performed using software Review Manager (Version 5.1.2) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by funnel plot, Egger's regression test and Begg's test. Sensitivity analysis was conducted by limiting the meta-analysis to the high quality studies (NOS score≥8).

Results

A total of 16 studies including 3,807 cases and 4,993 controls were combined showing no evidence of association between FXIII-A Val34Leu polymorphism and ischemic stroke (for Val/Leu vs. Val/Val : OR = 0.95, 95%CI = 0.77-1.16; for Leu/Leu vs. Val/Val: OR = 0.90, 95%CI = 0.73-1.11; for dominant model: OR = 0.97, 95%CI = 0.81-1.17; for recessive model: OR = 0.95, 95%CI = 0.77-1.17). In the subgroup analyses by study design, ethnicity and specific subtypes (small-vessel occlusive ischemic stroke and large-artery atherosclerotic ischemic stroke ), there was lack of evidence for the association.

Conclusions

This meta-analysis indicates that there is no evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke.     

Association between adiponectin gene polymorphisms and coronary artery disease across different populations

Objective

Many studies have suggested that adiponectin gene might be involved in the development of coronary artery disease (CAD). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to assess the associations of + 45T/G, + 276G/T and − 11377C/G polymorphisms in adiponectin gene with CAD susceptibility.

Methods

Published literature from PubMed and EMBASE databases were searched. Pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated using fixed- or random-effects model.

Results

Sixteen studies (4394 cases / 8187 controls) for + 45T/G polymorphism, fifteen studies (3569 cases / 7463 controls) for + 276G/T polymorphism, and thirteen studies (3531 cases / 7072 controls) for − 11377C/G polymorphism were included in the meta-analysis. The overall results showed that there was a statistically significant association between − 11377C/G polymorphism and CAD (G vs. C: OR = 1.15, 95%CI 1.07-1.24).Similar results were observed among European (G vs. C: OR = 1.11, 95%CI 1.02-1.20) and East Asian populations (G vs. C: OR = 1.27, 95%CI 1.11-1.45). However, no significant association was found for + 45T/G or + 276G/T polymorphism with CAD susceptibility.

Conclusions

The meta-analysis indicated the significant association of − 11377C/G polymorphism, but not + 45T/G or + 276G/T polymorphism, with CAD susceptibility. However, large-scale studies with the consideration of gene-gene and gene-environment interactions should be conducted to investigate the associations in future.     

Association of tissue plasminogen activator and plasminogen activator inhibitor polymorphism with myocardial infarction: A meta-analysis

Introduction

To investigate whether t-PA Alu repeat insertion/deletion (I/D) and PAI-1 4 G/5 G genetic variations are associated with the risk of MI.

Methods

We conducted a meta-analysis to assess the association between the t-PA I/D and PAI-1 4 G/5 G polymorphisms and risk of MI. We also performed subgroup analyses based on ethnicity (Caucasian, Asian, and African), gender and age. Forty one eligible studies including 12,461 cases and 14,993 controls were identified to evaluate the impact of PAI-1 4 G/5 G polymorphism on MI. Seven studies investigated the relationship between t-PA I/D and MI.

Results

This meta-analysis revealed that the PAI-1 4 G allele (4 G/4 G and 4 G/5 G genotype) was associated with an increased risk of MI compared with the 5 G allele in the overall population (OR = 1.094, 95% CI = 1.021 - 1.172, p = 0.011). The relative risks of MI for 4 G/4 G genotype was increased when compared to 5 G/5 G genotype and 5 G allele, with odds ratio at 1.157 (95% CI 1.015 - 1.320, p = 0.029) and 1.126 (95% CI = 1.015 - 1.249, p = 0.025). However, the results show that the 4 G/5 G polymorphism risk for MI was not associated with ethnicity stratification as Caucasian, Asian or African population. No substantial differences in the genotype distributions were observed in the MI group and control group along the lines of gender and age. After multivariable analysis t-PA I/D polymorphism showed no consistent association with MI.

Conclusions

This study suggests that the 4 G/5 G polymorphism of PAI-1 may be a risk factor for MI in overall populations.     

Association of PDE4D and IL-1 gene polymorphism with ischemic stroke in a Han Chinese population

Background

The single-nucleotide polymorphisms (SNPs) of the phosphodiesterase 4D (PDE4D) and interleukin-1 (IL-1) genes are associated with increased risk for the development of ischemic stroke (IS) in whites. However, little is known about whether this association could also occur in Han Chinese.

Method

A total of 371 patients with IS and unrelated healthy controls were recruited and the SNPs of the PDE4D (83T/C), (87T/C), IL-1 (−889C/T) and IL-1 (−511C/T) were characterized, respectively, by polymerase chain reactions-restriction fragment length polymorphism (PCR-RFLP). The genotype and allele frequencies of these SNPs in this population were statistically analyzed.

Results

The genotype and allele frequencies of the PDE4D (87T/C) and IL-1 (−511C/T) were similar between IS patients and controls. In contrast, the frequencies of CC genotype and C allele of the PDE4D (83T/C) and the T allele frequency of IL-1 (−889C/T) in IS patients were significantly higher than that in healthy controls (p = 0.001, p = 0.003 and p = 0.02, respectively), independent of the conventional risk factors. The values of odds ratio (OR) reached at OR = 1.603; 95%CI = 1.032-2.489; p = 0.036 for the CC genotype of the PDE4D (83T/C) and OR = 1.913; 95%CI = 1.621-2.375; p = 0.034 for the TT genotype of the IL-1 (−889C/T), respectively.

Conclusions

the SNPs of the PDE4D (83T/C) and IL-1 (−889C/T) were associated with increased risk for the development of IS in Northern Han Chinese.     

ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a meta-analysis

Introduction

The ABCB1 C3435T polymorphism limits oral bioavailability of clopidogrel and may influence prognosis of patients treated with clopidogrel. Several studies have examined the association between the C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients, but the results were inconsistent. To assess the role of the C3435T polymorphism in the impact on clinical outcomes, a meta-analysis was conducted.

Methods

6 studies with 10,153 subjects were included in this meta-analysis. Fixed- or random-effects model was chosen according to heterogeneity. Publication bias was evaluated by fail-safe numbers.

Results

The association of the C3435T polymorphism with risk of overall recurrent ischemic events in clopidogrel treated patients was not statistically significant for all genetic models (OR = 1.13, 95%CI: 0.78-1.64, P = 0.51; OR = 1.15, 95%CI: 0.99-1.33, P = 0.07; OR = 1.19, 95%CI: 0.81-1.76, P = 0.37). Significant association was identified between the C3435T polymorphism and risk of short-term recurrent ischemic events (OR = 1.55, 95% CI: 1.09-2.20, P = 0.01; OR = 1.41, 95% CI: 1.06-1.87, P = 0.02; OR = 1.77, 95% CI: 1.19-2.63, P = 0.005). No statistically significant association between the C3435T polymorphism and stent thrombosis (OR = 0.79, 95% CI: 0.47-1.32, P = 0.37) or bleeding (OR = 0.98, 95% CI: 0.79-1.21, P = 0.82) was identified. The results may be affected by publication bias.

Conclusions

This meta-analysis failed to show an association between the ABCB1 C3435T polymorphism and risk of overall recurrent ischemic events, stent thrombosis or bleeding in clopidogrel treated patients. However, the association between TT homozygotes of the C3435T polymorphism and risk of short-term recurrent ischemic events may exist, but needs more studies to confirm.     

A case-control study provides evidence of association for a common SNP rs974819 in PDGFD to coronary heart disease and suggests a sex-dependent effect

Introduction

Peden et al. have revealed a significant association between four new risk loci and coronary heart disease (CHD) in Europeans and South Asians. The goal of this study is to evaluate the contribution of these genetic loci to CHD risk in Han Chinese.

Methods

We recruited 161 CHD patients and 112 controls proved by angiography originated from Ningbo in the Eastern China, and performed a case-control association study of the four significant SNPs.

Results

Among the four tested SNPs, we found a significant association of rs974819 in PDGFD gene with CHD (allele p = 0.04; OR = 1.45, 95% CI = 1.02 - 2.08) and the allele A/G of rs974819 shows significant difference in females (allele p = 0.04; OR = 1.83, 95% CI = 1.01 - 3.31). A further meta-analysis showed that rs974819 of PDGFD gene was significantly associated with an increasing risk of CHD (OR = 1.08, 95% CI = 1.05 - 1.11) in both Europeans and South Asians including Han Chinese.

Conclusions

Our findings suggests that rs974819 of PDGFD is also a CHD risk factor in Han Chinese. In addition, it presents a sex-dependent genetic effect.     

FCGR2A rs1801274 polymorphism is associated with risk of childhood-onset idiopathic (immune) thrombocytopenic purpura: Evidence from a meta-analysis

Introduction

Previous studies have evaluated the association between FCGR2A H131R (rs1801274) polymorphism and idiopathic (immune) thrombocytopenic purpura (ITP), but results remain inconsistent. This meta-analysis was conducted to clarify these controversies.

Methods

Literatures on PubMed/ Medline, Embase and CENTRAL databases up to September 2013 were searched by two investigators. The distributions of alleles and genotypes between cases and controls were compared by using odds ratios (ORs) and 95% confidence intervals (95% CIs). Fixed or Random-effects models were used when appropriate.

Results

10 studies involving 553 patients and 1088 controls were available for this study, including 7 studies of Caucasian descendents, 2 studies of Asian descendents, and 1 study contained diverse ethnicity. In this studied overall population, we didn’t found any significant association between the FCGR H131R polymorphism and the risk of ITP for all genetic models. But in the subgroup analysis, a significant association between FCGR H131R polymorphism and ITP susceptibility was observed in Caucasian population of childhood-onset group for H vs. R (OR = 1.246, 95% CI 1.021-1.522, p = 0.031), HH vs. HR + RR (OR = 1.562, 95% CI 1.145-2.129, p = 0.005), HH vs. HR (OR = 1.598, 95% CI 1.146-2.228, p = 0.006), HH vs. RR (OR = 1.484, 95% CI 1.005-2.191, p = 0.047). No significantly between-study heterogeneity was observed for all genotype models in Caucasian childhood-onset ITP subtype analysis. However, this association was not stable after sensitivity analysis.

Conclusion

Our present meta-analysis indicated that FCGR H131R polymorphism might not be associated with risk of ITP in overall population. However, in Caucasian childhood-onset subgroup, there might be an association between FCGR2A H131R polymorphism and ITP risk, which is not robust and should be explained with caution.     

Tumor necrosis factor-alpha G-308A gene polymorphism and coronary heart disease susceptibility: an updated meta-analysis

Purpose

Several studies have reported apparently conflicting findings for the effects of tumor necrosis factor-alpha (TNF-α) G-308A polymorphism on coronary heart disease (CHD) susceptibility. We undertook a systematic review and meta-analysis to investigate the association between this gene variant and CHD predisposition.

Methods

We systematically searched electronic databases (Medline, EMbase, Chinese BioMedical, BIOSIS, Global Health, PsycINFO, Allied and Complementary Medicine Database, Cochrane Library, HuGE Navigator, and British Nursing) for relevant studies published between 1947 and October, 2010. Summarized estimation of odds ratio (OR) and 95% confidence interval (CI) were calculated. Publication bias and heterogeneity among studies were explored.

Results

We identified 24 studies providing data for 9 921 cases and 7 944 controls. Pooled analysis based on ORs adjusted by CHD risk factors showed that carrying the TNF-α gene A variant conferred a 1.5-fold increased risk of developing CHD (AG + AA vs. GG, OR = 1.50, 95% CI: 1.23-1.77) in Caucasian population. No significant association between the gene polymorphism and CHD risk could be found in other ethnic groups.

Conclusions

It is probable that carrying the A variant is associated with CHD risk in Caucasians but not in Asians, Indians, or Africans. Further studies are merited to assess the association in greater details, especially in Asians, Indians and Africans.     

Lack of association between TLR4 Asp299Gly polymorphism and atherosclerosis: evidence from meta-analysis

Introduction

Toll like receptor 4 (TLR4) expression was found to increase markedly in human atherosclerotic lesions, notably on macrophages and endothelial cells. TLR4 Asp299Gly polymorphism was associated with a blunted receptor activity and a subsequently diminished inflammatory response, and may subsequently reduce atherosclerosis (AS) risk. However, the results of molecular epidemiological studies remained inconsistent.

Materials and methods

The PubMed, CNKI databases were searched for all articles available. The OR corresponding to the 95% confidence interval (95% CI) was used to assess the association between TLR4 Asp299Gly polymorphism and risk of AS.

Results

15 case-control studies with 9,989 cases and 6,746 controls were available for this analysis. For control subjects, G allele frequency of TLR4 Asp299Gly polymorphism was ranging from 0.045 to 0.085. The G allele and the AG/GG genotypes were not associated with significantly risk of AS (OR = 1.02, 95% CI = 0.83 - 1.26 for G versus A and OR = 0.96, 95% CI = 0.80 - 1.15 for AG/GG versus AA, respectively) by random effects model.

Conclusion

These findings indicated that TLR4 Asp299Gly polymorphism may not play a role in AS development.     

Association of p22phox gene C242T polymorphism with coronary artery disease: A meta-analysis

Introduction

The C242T polymorphism of p22phox gene (rs4673) has been linked to the reduced coronary artery disease (CAD) risk, but results in the published literatures are controversial. A meta-analysis was performed to assess the effect of this polymorphism on the CAD risk.

Methods

A comprehensive search was conducted to identify all studies on the association of p22phox gene C242T polymorphism with CAD risk. The fixed or random effect pooled measure was selected based on the homogeneity test among studies. Heterogeneity among studies was evaluated using Q test and the I² of Higgins and Thompson. Meta-regression was used to explore the sources of between-study heterogeneity. Publication bias was estimated using modified Egger's linear regression test proposed by Harbord etal.

Results

We identified 15 published articles including 6273 CAD cases and 5045 controls. In this studied overall and non-Asian populations, we didn't found any significant association of p22phox gene C242T polymorphism with CAD in any of codominant, dominant, and recessive models. Only in Asian population, both fixed effect model (FEM) and random effect model (REM) indicated the significant protective effect both in codominant (FEM: OR = 0.771, 95%CI: 0.681-0.873; REM: OR = 0.751, 95%CI: 0.607-0.930) and dominant (FEM: OR = 0.714, 95%CI: 0.621-0.822; REM: OR = 0.694, 95%CI: 0.538-0.895) models with strong evidence for between-study heterogeneity (I² = 52.6% for codominant and I² = 56.5% for dominant), but not in recessive model. No evidence of publication bias was detected.

Conclusions

The results suggested a significant heterogeneity across ethnicities about the relationship between the T allele of p22phox gene C242T polymorphism and reduced CAD risk, with a significant protective effect only in Asian population that needs to be confirmed by further studies.     

The rs11833579 and rs12425791 polymorphisms and risk of ischemic stroke in an Asian population: A meta-analysis

Background

In 2009, a GWAS has confirmed that rs11833579 and rs12425791 near the NINJ2 gene could increase the stroke and ischemic stroke (IS) risk. Recently, several studies have been implemented to assess the relationship between the two SNPs and ischemic stroke risk in Asian. However, the results were poorly consistent. To study the association between the both polymorphisms and the risk of ischemic stroke, we performed a meta-analysis.

Methods

We used odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of association. The heterogeneity was checked by Q test and the inconsistency index (I²). Begg's test and Egger's test were used to assess the possible publication bias.

Results

Our study included 6 articles, contained 9 independent case-control studies, involved a total of 9,142 cases and 10,652 controls about rs11833579, 10,165 cases and 11,592 controls about rs12425791. There was a significant association between rs12425791 and IS risk with dominant genetic model (OR = 1.087, 95%CI = 1.021-1.158, I² = 34.6%, P = 0.152), but not with recessive genetic model and allele A vs. allele G. For rs11833579, we failed to verify it relate with IS risk under allele A vs. allele G, dominant and recessive genetic model.

Conclusions

This meta-analysis suggest that rs12425791 is relative to ischemic stroke risk under dominant model in Asian population, but not for rs11833579.     

Association between PAI-1 4G/5G Polymorphisms and osteonecrosis of femoral head: A Meta-analysis

Background

The polymorphism of the plasminogen activator inhibitor-1 (PAI-1) 4G/5G gene has been correlated with susceptibility to osteonecrosis of the femoral head (ONFH), but study results are controversial. The aim of this study was to derive a more precise estimation of the relationship between the PAI-1 4G/5G Gene polymorphism and ONFH by performing a meta-analysis.

Methods

The meta-analysis was based on five eligible case-control studies involving 419 cases and 969 controls and summarized data indicating the association between PAI-1 polymorphism and risk of osteonecrosis of the femoral head. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to assess the strength of this association in the random-effects model or fixed-effects model.

Results

A significant association between PAI-1 4G/5G polymorphism and ONFH susceptibility was observed for 4G4G + 4G5G vs. 5G5G (OR = 1.766, 95% CI 1.279–2.437, P = 0.001), 4G/4G vs. 4G/5G + 5G/5G (OR = 2.050, 95% CI 1.581–2.657, P = 0.000), 4G/4G vs. 5G/5G (OR = 2.553, 95% CI 1.345–4.846, P = 0.004), and 4G vs. 5G (OR = 1.758, 95% CI 1.236–2.500, P = 0.002). No significant association between PAI-1 4G/5G polymorphism and ONFH susceptibility was observed for 4G/5G vs. 5G/5G (OR = 1.327, 95% CI 0.939–1.877, P = 0.109).

Conclusions

This meta-analysis suggested that 4G/5G polymorphism of the PAI-1 gene was a risk factor for ONFH. This study also suggests that the PAI-1 4G4G genotype may indicate a risk for ONFH.     

The role of soluble P selectin in the diagnosis of venous thromboembolism

Introduction

Soluble P selectin (sPsel), a member of the selectin family of cell adhesion receptors, has been proposed as a key molecule in hemostasis and thrombosis mediating platelet rolling, generating procoagulant microparticles and enhancing fibrin deposition. The aim of this study was to examine the role of sPsel in the diagnosis of venous thromboembolism (VTE).

Materials and Methods

We performed a systematic review and we used meta-analysis to synthesize data from published studies reporting sPsel levels in patients with i) VTE (deep venous thrombosis; DVT or DVT and pulmonary embolism; PE) and ii) DVT only. Pooled Odds Ratios (ORs) with 95% Confidence Intervals (CIs) were appropriately calculated among patients and controls. Diagnostic performance of sPsel was tested with pooled sensitivity, specificity, Diagnostic Odds Ratio (DOR) and summary receiver operator characteristic (SROC) curve.

Results

Eleven studies, comprising of 586 VTE patients and 1,843 controls were deemed eligible. The sPsel was significantly increased after VTE (OR = 2.89, 95%CI = 2.31-3.61, p < 0.001), or DVT only (OR = 2.64, 95%CI = 1.95-3.56, p < 0.001). Subgroup analysis evidenced that sPsel was also increased after VTE when evaluating only studies with patients that had no prior medical history (OR = 2.88, 95%CI = 1.98-4.19, p < 0.001). Exclusion of studies including patients with solid organ tumor, HIV or lupus anticoagulants positive patients did not alter findings. Pooled sensitivity and specificity of sPsel was 0.57 (95%CI = 0.30-082, p < 0.001) and 0.73 (95%CI = 0.51-0.90, p < 0.001), respectively and DOR was 4.31 (95%CI = 2.22-8.37, p < 0.01). SROC curve yielded in significant accuracy of sPsel performance (AUC = 0.74, p = 0.05).

Conclusions

The sPsel was significantly elevated in patients with DVT, both uncomplicated and complicated with PE and presented with high levels of diagnostic performance. sPsel is a plasma biomarker that may help in the diagnosis of VTE.     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: A meta-analysis

Introduction

The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies.

Materials and Methods

A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6^th 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0.

Results

A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR = 1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR = 1.60, 95%CI: 1.24-2.06, P = 0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR = 2.08, 95%CI: 1.29-3.35, P = 0.003) and Caucasians (dominant model: OR = 1.31, 95%CI: 1.10-1.56, P = 0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR = 1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery.

Conclusion

Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders.     

Role of serotonergic-related systems in suicidal behavior: Data from a case-control association study

Objective

To investigate whether functional polymorphisms directly (HTR2A and SLC6A4 genes) or indirectly (IL-1 gene complex, APOE and ACE genes) related with serotonergic neurotransmission were associated with suicidal behavior.

Subjects and methods

227 suicide attempters, 686 non-suicidal psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods.

Results

There were no differences in genotype frequencies between the three groups. The −1438A/G [χ² (df) = 9.80 (2), uncorrected p = 0.007] and IL-1α −889C/T [χ² (df) = 8.76 (2), uncorrected p = 0.013] genotype frequencies between impulsive and planned suicide attempts trended toward being different (not significant after Bonferroni correction). Suicide attempts were more often impulsive in the presence of −1438G/G or IL-1α −889C/T or C/C genotypes. There was interaction between the polymorphism 5-HTTLPR and age [LRT (df) = 6.84 (2), p = 0.033] and between the polymorphisms APOE and IL-1RA (86 bp)_n [LRT (df) = 12.21 (4), p = 0.016] in relation to suicide attempt lethality.

Conclusion

These findings further evidence the complexity of the association between genetics and suicidal behavior, the need to study homogenous forms of the behavior and the relevance of impulsive and aggressive traits as endophenotypes for suicidal behavior.     

Risk factors for hospital-sssociated venous thromboembolism in the neonatal intensive care unit

Objective

To determine hospital-associated venous thromboembolism (HA-VTE) risk factors in critically ill neonates.

Methods

We conducted a case-control study in the neonatal intensive care unit (NICU) of All Children’s Hospital Johns Hopkins Medicine (St. Petersburg, FL), from January 1, 2006 - April 10, 2013. We identified HA-VTE cases using electronic health record. Four NICU controls were randomly selected for each HA-VTE case. Associations between putative risk factors and HA-VTE were estimated using odds ratios (ORs) and ninety-five percent confidence intervals (95%CIs) from univariate and multivariate regression analyses.

Results

Twenty-three HA-VTE cases and 92 controls were included. The annual HA-VTE incidence was approximately 1.4 HA-VTE cases per 1,000 NICU admissions. In univariate analyses, mechanical ventilation (OR = 7.27, 95%CI = 2.02-26.17, P = 0.002), central venous catheter (CVC; OR = 52.95, 95%CI = 6.80-412.71, P < 0.001), infection (OR = 7.24, 95%CI = 2.66-19.72, P < 0.001), major surgery (OR = 5.60, 95%CI = 1.82-17.22, P = 0.003) and length of stay ≥ 15 days (OR = 6.67, 95%CI = 1.85-23.99, P = 0.004) were associated with HA-VTE. Only CVC (OR = 29.04, 95%CI = 3.18-265.26, P = 0.003) remained an independent risk factor in the multivariate analysis. Based on this result, the estimated risk of HA-VTE in NICU patients with a CVC was 0.9%.

Conclusion

This study identifies CVC as an independent risk factor for HA-VTE in critically ill neonates. However, the level of risk associated with CVC is below the conventional threshold for primary anticoagulation thromboprophylaxis. Larger studies are needed to substantiate these findings and identify novel putative risk factors to further distinguish NICU patients at highest HA-VTE risk.     

MTHFR and the risk for cerebral venous thrombosis- a meta-analysis

Background

The association between methylenotetrahydrofolate reductase (MTHFR) 677TT and the increased risk of venous thrombosis is uncertain. Studies of this polymorphism in cerebral venous thrombosis (CVT) are inconclusive.

Objectives

With a systematic review, we aimed to collect all case-control studies comparing the frequency of this polymorphism in CVT patients (cases) and healthy controls.

Methods

We used the MEDLINE, Cochrane Library and the ISI web of knowledge electronic databases and reference lists of retrieved articles in order to identify published case-control studies that evaluated the presence of MTHFR 677C>T polymorphism in CVT. Two reviewers independently selected studies. We compared the frequency of 677TT between cases and controls using the Mantel-Haenszel method, a fixed and a random-effects model in the pooled data.

Results

Nine case-control studies were included. The pooled analysis included 382 patients with CVT and 1217 controls. The frequency of 677TT genotype among CVT patients was not significantly higher compared with controls (15.7% versus 14.6%; OR = 1.12, 95% confidence interval (95% CI) 0.80 to 1.58; p = 0.50). There was significant heterogeneity between studies.

Conclusions

This meta-analysis confirmed that there is currently insufficient data supporting that 677TT genotype is a risk factor for CVT. These results imply a continuing searching for the cause of CVT in patients with this polymorphism.