Exosomal circCNOT6L Regulates Astrocyte Apoptotic Signals Induced by Hypoxia Exposure Through miR99a-5p/SERPINE1 and Alleviates Ischemic Stroke Injury.

Circular RNAs are involved in intervention strategies for treating ischemic stroke (IS). However, circCNOT6L (hsa_circ_0006168) has not yet been reported in IS. Thus, we aimed to explore the potential role of circCNOT6L and its molecular mechanism in IS. In this study, we first found that the expression of both exosomal circCNOT6L (P = 0.0006) and plasma circCNOT6L (P = 0.0054) was down-regulated in IS patients compared with controls. Clinically, a negative correlation was observed between the relative expression level of circCNOT6L and the National Institutes of Health Stroke Scale (NIHSS) score and infarct volume of the brain. Simultaneously, the relative expression level of circCNOT6L was negatively associated with multiple risk factors for IS, such as mean platelet volume (MPV), red cell distribution width (RDW), very low-density lipoprotein (VLDL), and serum potassium, whereas it was positively correlated with high-density lipoprotein (HDL). In vitro, circCNOT6L silencing blocked cell viability and proliferation, while it promoted cell apoptosis of astrocytes undergoing oxygen-glucose deprivation/reperfusion (OGD/R) treatment. Mechanistically, the RNA antisense purification (RAP) assay and luciferase reporter assay revealed that circCNOT6L acts as a miRNA sponge to absorb miR-99a-5p and then regulates the expression of serine proteinase inhibitor (SERPINE1). In the further rescue experiment, overexpressing SERPINE1 could rescue the cell apoptotic signals due to circCNOT6L depletion. In conclusion, CircCNOT6L attenuated the cell apoptotic signal of astrocytes via the miR99a-5p/SERPINE1 axis and then alleviated injury after hypoxia induced by ischemic stroke.

Analysis of expression profiles and bioinformatics suggests that plasma exosomal circular RNAs may be involved in ischemic stroke in the Chinese Han population.

Circular RNAs (circRNAs) have been confirmed to be associated with ischemic stroke(IS), but the involvement of exosomal circRNAs in plasma still needs to be extensively discussed. Therefore, we aimed to investigate the expression profile of exosomal circRNAs in plasma and the potential roles and mechanisms of exosomal circRNAs in the pathogenesis of ischemic stroke in the Chinese Han population. In this study, the plasma exosomal circRNA expression profiles of three IS patients and three healthy controls were analyzed using circRNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and circRNA-miRNA-mRNA regulatory network analysis were performed for the aberrantly expressed genes. Protein-protein interaction (PPI) networks and molecular complex detection algorithms (MCODEs) were analyzed by STRING and Cystoscope for functional annotation and construction, respectively. RNA-Seq analysis revealed that a total of 3540 circRNAs were aberrantly expressed in exosomes, 1177 circRNAs were significantly upregulated, and 2363 circRNAs were downregulated in IS patients compared to healthy controls. Bioinformatics analysis revealed that the parental genes of differentially expressed circRNAs as well as the mRNAs predicted in the circRNA-miRNA-mRNA regulatory network are enriched for signaling pathways associated with IS pathology, such as the MAPK signaling pathway, lipid and atherosclerosis, neurotrophic factor signaling pathways, mTOR signaling pathway, the p53 signaling pathway etc. Then, 10 hub genes were identified from the PPI and module networks, including FBXW11, FBXW7, UBE2V2, ANAPC7, CDC27, UBC, CDC5L, POLR2H, POLR2F and RBX1. Overall, the present study provides evidence of an altered plasma exosomal circRNA expression profile and its potential function in IS. Our findings may contribute to the study of the pathogenesis of circRNAs in IS and provide ideas for studying potential diagnostic biomarkers and therapeutic targets for IS.

Association of CHUK gene polymorphism and ischemic stroke in the Han Chinese population.

BACKGROUND: Recently, the pivotal role of component of inhibitor of nuclear factor kappa B kinase complex (CHUK) in lipid levels and blood pressure has been reported, and hypertension and hyperlipidemia are common risk factors of ischemic stroke (IS). However, the association between CHUK and IS has not yet been explored. This study aims at evaluating the relationship of CHUK polymorphisms (rs3808916, rs2230804 and rs3808917) and IS risk as well as IS-related risk factors. METHODS: CHUK mRNA expression was detected between 53 IS patients and 53 healthy controls using quantitative real-time polymerase chain reaction (qRT-PCR). A total of 816 IS patients and 816 age- and sex-matched healthy controls were genotyped using the Sequenom MassARRAY iPLEX platform. RESULTS: CHUK mRNA was highly expressed in IS patients compared with healthy subjects (P＜0.001). No significant associations were observed between rs3808916, rs2230804, rs3808917 and IS susceptibility (P＞0.05). Moreover, haplotype analysis showed that no haplotype of CHUK polymorphisms was associated with IS (P > 0.05). However, rs2230804 was related to diastolic blood pressure (DBP) of IS patients (P = 0.035), while rs3808917 was associated with triglyceride (TG) levels (P = 0.046). CONCLUSIONS: The CHUK expression is involved in the development of IS. CHUK variants rs2230804, and rs3808917 may affect blood pressure and lipid levels of IS patients. However, CHUK rs3808916, rs2230804 and rs3808917 polymorphisms are not associated with IS risk.

LncRNA H19 rs4929984 Variant is Associated with Coronary Artery Disease Susceptibility in Han Chinese Female Population.

Long non-coding RNAs (lncRNAs) have been reported to play an important role in cardiovascular diseases. The present study aimed to investigate the levels of lncRNA H19 in patients with coronary artery disease (CAD) and the genetic association of lncRNA H19 rs217727 and rs4929984 polymorphisms with CAD susceptibility. We detected an upregulated expression of lncRNA H19 in the peripheral blood of CAD patients compared with healthy controls, and the area under the receiver operating characteristic curve of lncRNA H19 for CAD diagnosis was 0.918. In addition, rs4929984 was associated with the susceptibility of Han Chinese females to CAD, as shown in the additive and dominant models, and the significant association remained after adjusting for age and Bonferroni correction. The A allele carriers of rs4929984 were correlated with females' susceptibility to CAD compared with the C allele, and the A-G haplotype of rs4929984-rs217727 was associated with females' susceptibility to CAD. Furthermore, rs217727 and rs4929984 were associated with the levels of clinicopathological parameters of CAD cases. We suggest that lncRNA H19 has a potential to be a diagnostic biomarker for CAD; rs4929984 polymorphism is associated with females' susceptibility to CAD in the Han Chinese population, and lncRNA H19 variants may influence lipid metabolism, inflammation, and coagulation function of CAD patients.

Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke.

BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) are potential biomarkers of tumors, cardiac disease, and cerebral disease because of their interaction with coding RNAs. This work focused on ischemic stroke (IS) and aimed to identify novel lncRNA biomarkers and construct lncRNA-related networks in IS. METHODS: Differentially expressed lncRNAs were identified using Arraystar Human LncRNA Microarray v4.0, and validated with qRT-PCR. A lncRNA-mRNA co-expression network and a lncRNA-miRNA-mRNA regulatory network were constructed. Functional and pathway analyses were then performed. RESULTS: In total, 560 up-regulated and 690 down-regulated differentially expressed lncRNAs were found (P < 0.05, false discovery rate < 0.05, absolute fold change ≥ 2). qRT-PCR results confirmed that lncRNA-ENST00000568297, lncRNA-ENST00000568243, and lncRNA-NR_046084 exhibited significant differential expression between IS and controls (all P < 0.05). Areas under the curves (AUCs) for these lncRNAs were 0.733, 0.743, and 0.690, respectively, and the combined AUC was 0.843. A coding-noncoding co-expression (CNC) network was constructed based on Pearson's correlation coefficient. A specific lncRNA-miRNA-mRNA regulatory network of ENST00000568297, ENST00000568243, and NR_046084 was also constructed. Functional annotation of the up- and down-regulated mRNAs was performed. Pathway analysis enriched IS-related pathways with mRNAs in the lncRNA-miRNA-mRNA regulatory network. CONCLUSION: LncRNA and mRNA expression profiles in human peripheral blood were altered after IS. ENST00000568297, ENST00000568243, and NR_046084 were identified as novel potential diagnostic biomarkers of IS. Analysis of the CNC network and lncRNA-miRNA-mRNA regulatory network suggested that lncRNAs may participate in IS pathophysiology by regulating pivotal miRNAs, mRNAs, or IS-related pathways.

TLR4 polymorphisms affect stroke risk and inflammatory response in Chinese ischemic stroke patients.

This study aimed to evaluate the association of the toll-like receptor 4 (TLR4) polymorphisms rs1927914, rs10759932, and rs11536889 with susceptibility to ischemic stroke (IS) and the serum levels of inflammatory cytokines. A total of 816 IS patients and 816 control subjects were genotyped using Sequenom MassARRAY technology. The serum levels of interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNFα) were measured by enzyme-linked immunosorbent assay. rs1927914 was significantly associated with male IS patients in the additive model [odds ratio (OR) = 0.81; 95% confidence interval (CI) = 0.67-0.99; P = 0.039] and in the allele model (OR = 0.81; 95% CI = 0.66-0.99; P = 0.037). In the dominant model, rs10759932 was significantly associated with the serum TNFα level of the male IS patients [regression coefficient (ß) = 0.15; 95% CI = 0.01-0.29; P adj = 0.042]. This polymorphism was also correlated with the serum IL-8 level of female IS patients in the additive model (ß = 0.24; 95% CI = 0.25-0.43; P adj = 0.021) and in the recessive model (ß = 0.65; 95% CI = 0.11-1.11; P adj = 0.026). The TLR4 gene rs1927914 polymorphism was associated with susceptibility to IS in males. Moreover, the rs10759932 polymorphism may affect inflammatory response in IS patients.

Association of NKAPL, TSPAN18, and MPC2 gene variants with schizophrenia based on new data and a meta-analysis in Han Chinese.

BACKGROUND: Schizophrenia (SZ) is suggested to be a complex polygenetic disorder with high heritability. Genome-wide association studies have found that the rs1635, rs11038167, and rs10489202 polymorphisms are associated with SZ in Han Chinese. However, results of validation studies are inconsistent. This study aimed to test the association between the NKAPL rs1635, TSPAN18 rs11038167, and MPC2 rs10489202 polymorphisms and SZ in a Chinese population. METHODS: This study contained 700 unrelated SZ patients (300 Zhuang and 400 Han) and 700 gender- and age-matched controls (300 Zhuang and 400 Han). The polymorphisms in TSPAN18 (rs11038167), NKAPL (rs1635), and MPC2 (rs10489202) were genotyped using the Sequenom MassARRAY method. Statistical analyses were performed with PLINK program and SPSS l6.0 for Windows. STATA11.1 was used for meta-analysis. RESULTS: No statistically significant difference was found in different allele and genotype frequencies of rs1635, rs11038167, and rs10489202 between SZ cases and controls of Zhuang and Han ethnicities and the total samples (all p>0.05). Further meta-analysis suggested that single-nucleotide polymorphism rs10489202 was significantly associated with SZ in a Han Chinese population (p OR=0.002). CONCLUSIONS: Our case-control study failed to validate the significant association of NKAPL rs1635, TSPAN18 rs11038167, and MPC2 rs10489202 polymorphisms with SZ susceptibility in the southern Zhuang or Han Chinese population. However, meta-analysis showed a significant association between MPC2 variant rs10489202 and SZ susceptibility in Han Chinese.

TLR7 rs2897827 Polymorphism Affects TLR7 Gene mRNA Expression and Serum Apolipoprotein A1 Level of Ischemic Stroke Patients in a Chinese Han Population.

Stroke is a multi-factorial disorder that has become the leading cause of death and disability worldwide. Previous studies reported that TLR7 mRNA expression is associated with poor outcome of ischemic stroke (IS). This study aimed to assess whether TLR7 mRNA expression affects IS occurrence, as well as the association of TLR7 rs2897827 with susceptibility to IS and TLR7 mRNA expression and serum apolipoprotein and lipid levels in a Chinese Han population. A total of 816 stroke patients and 816 healthy controls were included in this study. mRNA expression was determined by quantitative real-time PCR. The Sequenom MassARRAY iPLEX platform was used to genotype the TLR7 rs2897827 polymorphism. TLR7 mRNA expression of the IS cases was statistically significantly higher than that of the controls in the male or female group (male, P = 0.014; female, P = 0.025). In the male IS cases, TLR7 mRNA expression of the T allele carriers was statistically significantly higher than that of the C allele carriers (P = 0.018). However, a significant difference was not observed in the female cases (P = 0.545). In either the male or female group, the distribution of genotype or allele had no statistical significance (P > 0.050). The ApoA1 level of the T carriers was statistically significantly higher than the C carriers in males (t = -2.383, P = 0.020); however, the ApoB and lipid levels were not associated with rs2897827 (P > 0.050). In female patients, no significant difference was observed between different genotypic/allelic carriers in serum apolipoprotein and lipid levels (all P > 0.050). The expression of the TLR7 gene may affect IS occurrence. TLR7 gene rs2897827 may influence TLR7 mRNA expression and the plasma ApoA1 level in male IS patients.

Impact of TLR5 rs5744174 on stroke risk, gene expression and on inflammatory cytokines, and lipid levels in stroke patients.

Many studies reported that toll-like receptors (TLRs) played an important role in the process of ischemic stroke (IS). However, the impact of TLR5 rs5744174 on stroke risk, gene expression and on inflammatory cytokines, and lipid levels in ischemic stroke patients has not yet been reported and was therefore the subject of this study. In this case-control study, a total of 816 ischemic stroke patients and 816 healthy controls were genotyped using Sequenom MassArray technology. The mRNA expression of TLR5 was detected through quantitative real-time PCR among 52 ischemic stroke patients. The levels of IL-1b, IL-6, IL-8, and TNFα were measured by ELISA among 62 IS patients. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were determined among 816 IS patients using a Hitachi 7600 Automatic Biochemistry Analyzer. Our result showed TLR5 rs5744174 polymorphism was not associated with stroke risk, TLR5 mRNA expression and inflammatory cytokines of IS patients (P > 0.050), but was significantly associated with HDL-C (recessive model: ß = - 0.14, 95 % CI: -0.24 to -0.03, P = 0.009). TLR5 rs5744174 polymorphism may have no impact on the stroke risk, gene expression and inflammatory cytokines, but may influence the HDL-C serum level of IS patients in Chinese Han population.

The dopamine beta-hydroxylase gene polymorphism rs1611114 is associated with schizophrenia in the Chinese Zhuang but not Chinese Han population.

Schizophrenia (SCZ) is a devastating neurodevelopmental disorder. However, the mechanism underlying this highly heritable disorder remains unclear. The dopamine beta-hydroxylase (DBH) gene encodes a key metabolic enzyme of dopamine. Consequently, DBH is considered a candidate gene for SCZ. However, previous studies on its association with SCZ susceptibility have shown conflicting results. Here, we examined association between the rs1611114 polymorphism of DBH and SCZ susceptibility and related clinical symptoms. A total of 691 SCZ patients and 698 age- and gender-matched healthy controls were examined. mRNA expression levels of DBH were measured by quantitative real-time polymerase chain reaction, and the rs1611114 polymorphism was genotyped using the Sequenom MassARRAY platform. Also, the Positive and Negative Syndrome Scale (PANSS) was used to assess SCZ clinical symptoms. Our results show lower DBH mRNA expression levels in SCZ patients than healthy controls (Zhuang: p = 0.000; Han: p = 0.037). Interestingly, the rs1611114 polymorphism was significantly associated with SCZ susceptibility (overdominant model: p = 0.010) in only the Chinese Zhuang population. Furthermore, the rs1611114 polymorphism was associated with PANSS total score (allele T/C: p = 0.015) and general psychopathology score (allele T/C: p = 0.027) in Chinese Zhuang SCZ patients. These results suggest that the DBH gene may play an important role in the occurrence of SCZ. Also, rs1611114 may be associated with SCZ susceptibility and related clinical symptoms in the Chinese Zhuang but not Han Chinese population. Further studies with larger samples of different ethnicities are needed to confirm the role of DBH in SCZ.

Analysis of Association between MAP2K4 Gene Polymorphism rs3826392 and IL-1b Serum Level in Southern Chinese Han Ischemic Stroke Patients.

BACKGROUND: Mitogen-activated protein kinase kinase 4 (MAP2K4) gene acts as the direct upstream activator of c-Jun NH2-terminal kinase pathway, which plays an important role in regulating neuron survival and apoptosis in response to cerebral ischemia. However, the association between MAP2K4 gene polymorphisms and ischemic stroke (IS) has not yet been published. Therefore, this study investigates the association between MAP2K4 gene polymorphism rs3826392 and IS susceptibility, as well as its quantitative traits in Southern Chinese Han population. METHODS: A total of 816 Chinese patients with IS and 816 age- and sex-matched controls were recruited. Rs3826392 was genotyped using Sequenom MassARRAY iPLEX platform (Sequenom, San Diego, CA, USA). The mRNA expression of MAP2K4 gene in peripheral blood mononuclear cells was detected using reverse transcription-polymerase chain reaction. The levels of serum cytokines, including IL-1b, IL-6, IL-8, IL-12, and tumor necrosis factor-α (TNF-α), were measured by enzyme-linked immunosorbent assay. RESULTS: Significant association was not observed between MAP2K4 gene polymorphism rs3826392 and IS susceptibility in all genetic models (P > .05). A significant difference was found in IL-1b, IL-6, IL-8, and TNF-α serum levels between patients with IS and control groups. MAP2K4 gene polymorphism rs3826392 C/A genotype carriers showed significantly higher IL-1b serum levels compared with AA genotype carriers (P = .029) in patients with IS. CONCLUSION: MAP2K4 gene polymorphism rs3826392 did not contribute to IS susceptibility, but rs3826392 C/A genotype carriers showed significantly higher IL-1b serum levels. This result suggests that rs3826392 may play a potential role in the IS inflammatory process.

TNF-a (-238G/A and -308G/A) gene polymorphisms may not contribute to the risk of ischemic stroke.

BACKGROUND: The common and major pathological change in ischemic stroke is atherosclerosis in the artery. Tumor necrosis factor-a (TNF-a) is closely related to the pathogenesis of atherosclerosis. The aim of our study was to investigate whether TNF-a gene variants (-238G/A and -308G/A) are associated with ischemic stroke. METHODS: A total of 619 ischemic stroke patients and 612 controls were recruited to estimate the frequencies of two TNF-a (-238G/A and -308G/A) single nucleotide polymorphisms using a Sequenom MassARRAY time-of-flight mass spectrometer. The association between TNF-a gene polymorphisms and ischemic stroke risk was evaluated by computing the odds ratio (OR) and 95% Confidence Interval with multivariate unconditional logistic regression analyses. RESULTS: The OR results indicated that no significant associations were found between TNF-a gene (-238G/A and -308G/A) polymorphisms and the risk of ischemic stroke using five genetic models, including the allele model (A vs. G), co-dominant model 1 (GA vs. GG), co-dominant model 2 (AA vs. GG), the dominant model (AA+GA vs. GG), and the recessive model (GG+GA vs. AA). CONCLUSIONS: The TNF-a (-238G/A and -308G/A) gene polymorphisms may not be a susceptible predictor of ischemic stroke in Chinese populations.

Association of GWAS-supported loci rs2107595 in HDAC9 gene with ischemic stroke in southern Han Chinese.

BACKGROUND: Stroke is a multi-factorial disorder and has become the leading cause of death and disability worldwide. Recent genome-wide association studies (GWAS) have identified a significant association of single-nucleotide polymorphism (SNP) rs2107595 in HDAC9 gene with large-vessel ischaemic stroke (IS) in the European populations. The aim of this study is to examine the association of HDAC9 gene rs2107595 polymorphism with the susceptibility of IS in southern Han Chinese. METHODS: A case-control study was conducted in Chinese Han population, with a total of 1632 subjects including 816 stroke patients and 816 controls. Sequenom MassARRAY iPLEX was used to genotype the SNP rs2107595 in HDAC9 gene. Genetic association analysis between genotypes and risk of IS was evaluated by PLINK program. RESULTS: No significant association was found between the SNP rs2107595 and IS in the additive, dominant, recessive and allelic models (all p>0.050). For IS-related quantitative traits in the sex-stratified analysis, the results showed a significant association between rs2107595 and serum TG level of males in the additive model (padj=0.008) and the dominant model (padj=0.003), and a significant association of rs2107595 polymorphism with serum TC level of females in the additive model (padj=0.045) and the dominant model (padj=0.037). CONCLUSIONS: Our results indicate that HDAC9 variant rs2107595 may be not associated with IS risk in southern Han Chinese. However, the rs2107595 polymorphism may be associated with serum TC and TG level of IS patients.

Association Between TRAF6 Gene Polymorphisms and Susceptibility of Ischemic Stroke in Southern Chinese Han Population.

The tumor necrosis factor receptor-associated factor 6 (TRAF6) gene encodes a protein that acts downstream of the Toll-like receptor (TLR) pathway. TLRs activate inflammatory cascades and mediate inflammatory injury after cerebral ischemia. However, the role of TFAR6 gene polymorphisms in ischemic stroke (IS) remains unknown. This study aims to investigate the associations of TRAF6 gene polymorphisms with susceptibility to IS and IS-related quantitative traits in Southern Chinese Han population. A total of 816 IS cases and 816 age- and gender-matched controls were included. Two variants of the TRAF6 gene (rs5030411 and rs5030416) were genotyped using the Sequenom MassARRAY iPLEX platform. Our study showed that rs5030416 was significantly associated with increased susceptibility to IS in the additive model [ORadj 1.25(1.04-1.51), P adj = 0.019, P Bc = 0.038] and dominant model [ORadj 1.23(1.04-1.60), P adj = 0.021, P Bc = 0.042] after adjusting by age and sex and applying a Bonferroni correction. No significant association was found between rs5030411 and IS susceptibility (all P > 0.05). The haplotype rs5030416 (allele C)-rs5030411 (allele C) was significantly associated with IS susceptibility (P adj = 0.015). Moreover, a significant association of rs5030411 with TC levels in IS patients under the additive model [ß 0.16(0.01-0.30), P adj = 0.034] and recessive model [ß 0.45(0.12-0.78), P adj = 0.007] was observed after adjustment by age and sex. This association remained statistically significant under the recessive model (P Bc = 0.042) after Bonferroni correction. Our results suggest that TRAF6 gene polymorphisms may be involved in the pathogenesis of IS.

Association between the NOTCH4 gene rs3131296 polymorphism with schizophrenia risk in the Chinese Zhuang population and Chinese Han population.

BACKGROUND: Schizophrenia (SZ) is a common severe psychiatric disorder and a complex polygenic inherited disease that has not yet been fully interpreted. Heredity was proven to play an important role in the development of SZ. The association between the NOTCH4 gene rs3131296 polymorphism and SZ was reported to reach significance at the genome-wide level; therefore, it is necessary to replicate this association in other different populations. METHODS: To evaluate the association of the NOTCH4 gene rs3131296 polymorphism with the risk for SZ, and to explore whether a significant association could be replicated in different ethnic groups of China, we conducted this case-control study on 282 SZ cases (188 Han and 94 Zhuang) and 282 controls (188 Han and 94 Zhuang) among the Chinese Zhuang and Han populations. RESULTS: The results showed no statistically significant difference in the genotype or allele frequencies of the NOTCH4 gene variant rs3131296 between SZ patients and healthy controls in either the Zhuang or Han samples (p > 0.05). In addition, no significant difference was found in genotype or allele frequencies of the NOTCH4 gene variant rs3131296 between cases and controls in the combined samples including Zhuang and Han samples. CONCLUSIONS: Our study failed to replicate the significant association between the NOTCH4 gene rs3131296 polymorphism and the risk for SZ.

The ABCB1-C3435T polymorphism likely acts as a risk factor for resistance to antiepileptic drugs.

Previous studies have attempted to confirm the association between the ABCB1-C3435T polymorphism and drug-resistant epilepsy and produced discordant findings. A meta-analysis was conducted to assess the role of the C3435T polymorphism in drug-resistance in epilepsy. Databases were obtained from PubMed, Embase, the Chinese Wanfang, CNKI, and Chongqing VIP database, and all relevant studies were compiled up to February 2013. Odds ratios (ORs) were calculated using models of both fixed- and random-effects for comparisons of alleles and genotypes. Subgroup meta-analyses were carried out based on epilepsy subtype, age, therapeutic regimen, definition of drug-responsiveness and drug-resistance using alleles and genotypes models. Publication bias was tested by Begg's test and inverted funnel plot, and heterogeneity was checked by Cochran's Q statistic and the inconsistency index (I2). Cumulative meta-analyses were adopted to test the robustness of the findings. A total of 38 association studies including a total of 8716 subjects, 4037 drug-resistant patients and 4679 drug-responsive epilepsy patients were pooled in this meta-analysis. The association of ABCB1-C3435T with risk of drug-resistance was significant in the overall population (T allele vs. C allele, OR: 1.21; 95%CI: 1.06-1.39; P=0.006) and in Caucasians, adults, groups treated with various drugs, a '>10 seizures in a year' group based on resistance and a '≥2 years seizure free' group based on response subgroup analysis. The ABCB1-C3435T polymorphism is likely to act as a risk factor for resistance to antiepileptic drugs that needs to be confirmed through further studies.

Influence of the ß-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 ß-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.

Genetic polymorphism of ß-fibrinogen gene-455G/A can contribute to the risk of ischemic stroke.

Many studies have investigated the association between the ß-fibrinogen gene-455G/A (FGß-455G/A) polymorphism and the risk of ischemic stroke. However, these evidences were inadequate to provide stronger conclusions because most studies were generally small. To shed light on these inconclusive findings, we conducted a large sample size meta-analysis of studies relating to the FGß-455G/A polymorphism and the risk of ischemic stroke. Odds ratios with a 95 % confidence interval were used to investigate the association between FGß-455G/A polymorphism and ischemic stroke. Publication bias was tested by Egger's test and funnel plot. Inconsistency index and Cochran's Q statistic were used to check heterogeneity. Cumulative and recursive cumulative meta-analyses were performed to provide a framework for updating a genetic effect from all of the included studies. Twenty-six independent publications with 4,070 cases and 4,649 controls were included in this meta-analysis. Results showed that the ß-fibrinogen-455G/A polymorphism was significantly associated with the risk of ischemic stroke. The FGß-455G/A polymorphism was found to be a risk factor for ischemic stroke in Asians and adults, while association was not observed for Caucasians and juveniles based on the small size and it may be necessary to conduct larger studies on them to investigate the association in the future. The cumulative meta-analysis indicated a decline from 1998 to 2003, and the results remained stable during the period 2004-2012. The results indicate that FGß-455G/A polymorphism may be a susceptible predictor of ischemic stroke. More studies are needed to elucidate the relationship further.

The A640G polymorphism in the NAD(P)H oxidase p22phox gene (CYBA) is associated with risk reduction of coronary heart disease: a meta-analysis.

BACKGROUND: Recently, studies have focused on the association between the p22phox gene A640G polymorphism and coronary heart disease (CHD). However, the results are inconsistent. In this study, we aimed to further evaluate this association by using meta-analysis. METHODS: The PubMed, Embase, CBM, CNKI, WanFang and Chongqing VIP databases were searched for relevant articles. Hardy-Weinberg equilibrium (HWE) of the distribution of genotypes was tested using Pearson's chi-squared test. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were used to assess the strength of the association; Cochran's Q test and the I(2) statistic were used to evaluate heterogeneity. The random effects model and the fixed effects model were used according to heterogeneity; Begg's test and Egger's test were used to analyze publication bias. Sensitivity analysis was carried out to guarantee the stability of the results. Cumulative analysis was used to evaluate tendencies in the pooled OR. RESULTS: A total of eight articles including 3904 CHD cases and 3498 controls were included. A significant association between the A640G polymorphism and CHD was observed in codominant model 2 (AG versus AA: OR=0.86, 95% CI: 0.77-0.96). In the subgroup analysis, a significant association was observed between the A640G polymorphism and CHD in Caucasians, and in PB (population-based), non-PB, HWE (studies followed HWE) and non-HWE studies. CONCLUSIONS: Our results reveal that the A640G polymorphism may play a protective role in CHD.

The A930G polymorphism ofP22phox (CYBA) gene but not C242T variation is associated with hypertension: a meta-analysis.

BACKGROUND: Recently, it has been reported that the A930G and C242T polymorphisms within p22phox (CYBA) gene are involved in the pathogenesis of hypertension. However, the results remain controversial. Furthermore, no previous meta-analysis has been conducted to evaluate the relationship between the A930G and C242T polymorphisms and hypertension. Therefore, we performed this meta-analysis to clarify these controversies. OBJECTIVE AND METHODS: All of the included articles were retrieved from the PubMed and Embase databases, as well as the CNKI, CBM, Chongqing VIP and Wan Fang databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (OR) with corresponding 95% confidence intervals (CI) were used to assess the strength of the association. Accounting for heterogeneity, a fixed or random effects model was respectively adopted. Heterogeneity was checked using the Q test and the I(2) statistic. A cumulative meta-analysis was conducted to estimate the tendency of pooled OR. Funnel plots and Egger's tests were performed to test for possible publication bias. RESULTS: Five articles on A930G with 2003 cases/2434 controls and eight articles on C242T with 2644 cases/1967 controls were identified. A significant association of A930G polymorphisms with the risk of hypertension was found in the dominant model (OR=0.59, 95% CI: 0.38-0.92, p=0.021) and allelic model (OR=0.66, 95% CI: 0.46-0.95, p=0.024). In the stratified analysis, a significant association could be found among the hospital-based and population-based studies. However, no evidence of a significant association of the C242T polymorphism with hypertension was found in the overall analysis and subgroup analysis. CONCLUSIONS: This meta-analysis indicates that the A930G polymorphism, but not the C242T variation, might be a protective factor for hypertension.