Ischemic Stroke Susceptibility Research Articles

Association of TLR8 gene rs3764880 polymorphisms with susceptibility and lipid metabolism- and inflammation response-related quantitative traits of ischemic stroke in southern Chinese Han male population

Inflammatory response and lipid metabolism influence the development of ischemic stroke (IS). TLRs have an important function in inflammation and lipid metabolism. To investigate association of TLR8 rs3764880 polymorphism with susceptibility of IS and the relationship between rs3764880 with inflammation response- and lipid metabolism-related quantitative traits, we conducted a case–control study in a Han Chinese population comprising 816 cases and 816 controls being matched for age and gender. The distribution of allele of TLR8 rs3764880 had statistical significance in male group (P=0.017). The G allele carrier had a higher level of IL-8 (P=0.001, PBc=0.004) than the A allele carrier in male cases. Moreover, the rs3764880 genotype was significantly associated with TC (P=0.001, PBc=0.004) and LDL level (P=0.0002, PBc=0.0008) in the allele model, and the GG carrier had a higher LDL level (P=0.009, PBc=0.036) than the AA carrier in male patients. However, no statistically significant association was found between rs3764880 and any IS-related quantitative traits in female patients. Our study also revealed that IL-1b was associated with HDL (P=0.006, PBc=0.012) in IS patients. Therefore, TLR8 gene rs3764880 polymorphism might be associated with susceptibility and involved in the inflammatory reaction and lipid metabolism of IS in southern Chinese Han.

Influence of the Cyclooxygenase-2 Gene -765G/C and -1195G/A Polymorphisms on Development of Ischemic Stroke

Many studies have investigated the association between the cyclooxygenase-2 (COX-2) gene polymorphism and ischemic stroke. However, results of these studies still remain controversial. To better explain the association between COX-2 polymorphisms (-765G/C and -1195G/A) and ischemic stroke risk, a meta-analysis was performed. Relevant studies were identified from 4 Chinese databases (Chinese Biological Medical Literature database, Chinese National Knowledge Infrastructure database, Chongqing VIP database, and Chinese WANFANG database), PUBMED and EMBASE prior to December 2015. The strength of association between COX-2 polymorphism and ischemic stroke was evaluated by the odds ratio (OR) with 95% confidence interval (CI). Inconsistency index (I(2)) and the Cochran's Q statistic were used to check heterogeneity. Publication bias was evaluated by funnel plots and Egger's regression test. A total of 4086 ischemic stroke cases and 4747 controls were identified. Significant association between COX-2 -765G/C polymorphism and the risk of ischemic stroke was found in Brazilians and the African-Americans. The OR of (CC+GC versus GG) for the Brazilians and African-Americans were (6.328, 95% CI = 2.295-17.448) and (1.644, 95% CI = 1.060-2.551). In addition, the recessive model of the Brazilians gave an OR of 3.621 (95% CI: 1.519-8.630). Furthermore, the (GC versus GG) and the allele model of the African-Americans were (OR: 1.615, 95% CI = 1.015-2.572) and (OR: 1.422, 95% CI = 1.033-1.957). Significant association was also observed for COX-2 -1195G/A polymorphism in the subtypes of small vessel disease (SVD) of ischemic stroke. Our study suggests that COX-2 -765G/C and -1195G/A polymorphisms may contribute to susceptibility of ischemic stroke, specifically in Brazilians and the African-Americans, and those of SVD.

Association of XPF Levels and Genetic Polymorphism with Susceptibility to Ischemic Stroke.

OR = 1.877, 95% CI = 1.427-2.468). Similar results were obtained after adjusting for age, gender, and smoking status. Additionally, XPF plasma protein levels were significantly decreased in the CC/CT genotype compared with the TT genotype (P = 0.025). These data indicate that XPF might play an important role in the pathophysiological process of ischemic stroke, and the 30028T/C polymorphism might be associated with ischemic stroke susceptibility in a Chinese Han population.

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

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. 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. 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. 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.

A meta-analysis of adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility.

Several studies have investigated the correlation between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk. However, the results were not conclusive with each other. Therefore, to overcome this obstacle, we performed this meta-analysis to further explicate the adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility. Case-control or cohort studies focused on adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk were electronic searched in the databases of Medline, Pubmed, Cochrane library, Excerpta Medica database(EMBASE) and China National Knowledge Infrastructure (CNKI). All the potentially relevant studies were included in this meta-analysis. The association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke was expressed by odds ratio with its confidence interval. Publication bias has been assessed by begg’s funnel plot. All the analyses have been performed by Revman 5.1 statistical software. Finally, a total of six studies with 1,345 cases and 1,421 controls were included in this meta-analysis. Our results demonstrated that there was a significant association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk (p<0.05). People with G single nucleotide of adiponectin gene have the increased risk of developing ischemic stroke compared to T single nucleotide.

Association Between a Polymorphism (rs2071214) in Baculoviral IAP Repeat Containing 5 Gene (BIRC5) and Ischemic Stroke in Korean Population.

ObjectiveTo investigate whether baculoviral inhibitor of apoptosis (IAP) repeat containing 5 gene (BIRC5) polymorphisms are associated with the development and clinical phenotypes of ischemic stroke in Korea population.MethodsWe enrolled 121 ischemic stroke patients and 291 control subjects. Ischemic stroke patients were divided into subgroups according to the scores of National Institutes of Health Stroke Survey (<6 or ≥6) and Modified Barthel Index (<60 or ≥60). Single nucleotide polymorphisms (SNPs) of BIRC5 (rs3764383 and rs2071214) were selected and genotyped by direct sequencing for all subjects. Multiple logistic regression models (codominant 1 and 2, dominant, recessive, overdominant and log-additive) were used to estimate odds ratios (ORs), 95% confidence intervals (CIs), and p-values.ResultsIn analysis of stroke susceptibility, the genotype and allele frequencies of rs3764383 exhibited no difference between the control group and the ischemic stroke group. SNP rs2071214 was associated with ischemic stroke in the codominant (p=0.003), dominant (p=0.002), overdominant (p=0.005), and log-additive (p=0.008) models, respectively. The G allele frequency of rs2071214 was significantly (p=0.009) associated with susceptibility for ischemic stroke (OR, 1.57; 95% CI, 1.12–2.21). However, in the analysis for clinical phenotype, no SNP of the BIRC5 gene was found to be associated with ischemic stroke.ConclusionThese results suggest that a missense SNP (rs2071214) of BIRC5 may be associated with the development of ischemic stroke in the Korean population.

Association of Transforming Growth Factor Beta-1-509C/T Gene Polymorphism with Ischemic Stroke: A Meta Analysis.

Introduction:Transforming Growth Factor-Beta 1 (TGF-β1) is a pleiotropic cytokine with potent anti-inflammatory property, which has been considered as an essential risk factor in the inflammatory process of Ischemic Stroke (IS), by involving in the pathophysiological progression of hypertension, atherosclerosis, and lipid metabolisms. -509C/T TGF-β1 gene polymorphism has been found to be associated with the risk of IS. The aim of this meta-analysis was to provide a relatively comprehensive account of the relation between -509C/T gene polymorphisms of TGF-β1 and susceptibility to IS.Methods:A review of literature for eligible genetic association Studies published before October 20, 2014 was conducted in the PubMed, EMBASE, Google Scholar and Trip database. The strength of association was calculated by pooled odds ratios (ORs) with 95% confidence intervals using RevMan 5.3 software. Heterogeneity was examined using Higgins I-squared, Tau-squared, and Chi-squared tests.Results:A total of 2 studies involving 614 cases and 617 controls were found. The overall estimates did not show any significant relation between TGF-β1-509C/T polymorphism and risk of IS under dominant (CC+CT vs. TT: OR=1.01, 95%CI=0.31 to 3.26; P=0.99), recessive (CC vs. CT+TT: OR=0.94, 95%CI=0.47 to 1.90; P=0.87), and allelic models (T vs. C: OR=1.06, 95%CI=0.55 to 2.04; P=0.86).Conclusion:This meta-analysis showed that TGF-β1-509C/T gene polymorphism has no significant association with the susceptibility of IS. Further well-designed prospective studies with larger sample size are needed to confirm these findings.

A Polymorphism Within the 3'UTR of NLRP3 is Associated with Susceptibility for Ischemic Stroke in Chinese Population.

Stroke was regarded as a severe disorder with high morbidity and high mortality worldwide, ischemic stroke (IS) accounts for 85 to 90% of new increased stroke cases. Partial mechanisms were elucidated by genetic factors including genomic instability such as single nucleotide polymorphism (SNP). Previous reports demonstrated that inflammation was involved in IS, NLRP3 [nucleotide-binding domain (NOD)-like receptor protein 3], acting as a specific inflammatory gene, however, its function and influence on IS was not well clarified. In this study, a case-control study including 1102 IS patients and 1610 healthy controls was conducted to investigate the association between IS susceptibility with a SNP (rs10754558) in 3'UTR of NLRP3. Logistic regression analysis showed that the heterozygote and the homozygote GG confer a significantly increased risk of CRC after controlling for other covariates (adjusted OR=1.52, 95% C.I. 1.19-1.97, P=0.002; adjusted OR=2.22, 95% C.I. 2.18-3.67, P<0.001, respectively). Carriage of G allele was associated with a greatly increased risk of developing the disease (OR=1.69, 95% C.I. 1.31-1.83, P<0.001). Stratification analysis found that hypertension had interaction with rs10754558 to modulate IS risk. Further in vitro assay revealed that rs10754558 can affect mRNA level of NLRP3, suggesting its possible functional significance. Our data suggested that genetic polymorphisms in NLRP3 may influence IS risk in Chinese population. Replication of our studies in other populations and further functional studies are required for complete comprehension of the roles of NLRP3 polymorphisms in IS risk.

Associations of platelet-activating factor acetylhydrolase gene polymorphisms with risk of ischemic stroke.

Platelet-activating factor acetylhydrolase (PAF-AH) has an important function in the pathogenesis of ischemic stroke. The aim of the present study was to investigate the correlation between the variation of polymorphisms (R92H and V279F) in PAF-AH and ischemic stroke. A total of 375 patients with ischemic stroke and 370 healthy controls were recruited into the study. Polymorphisms of V279F and R92H in PAF-AH were detected by polymerase chain reaction and DNA direct sequencing method. No significant association was observed between V279F and ischemic stroke. However, the RH+HH genotype, RH genotype and H allele of R92H were significantly associated with an increased risk of ischemic stroke (P=0.02, P=0.03 and P=0.02, respectively), In addition, these correlations remained following adjustment for confounding risk factors of stroke. Furthermore, subgroup analysis showed that a significant association with R92H was identified in the large-artery atherosclerotic stroke subgroup. These findings indicated that variation of R92H in the PAF-AH gene may contribute to ischemic stroke susceptibility in the population studied.

A Meta-Analysis of the Association between Polymorphisms in MicroRNAs and Risk of Ischemic Stroke.

Ischemic stroke (IS) is responsible for a high death rate and for adult disability worldwide. MiR-146a (rs2910164), miR-149 (rs2292832), miR-196a2 (rs11614913) and miR-499 (rs3746444) are found to be associated with ischemic stroke. However, the results were inconsistent and inconclusive. The present study performed a meta-analysis to get a more precise and comprehensive estimation of the association between the four polymorphisms and IS risk. The databases Pubmed, Embase, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, and Chinese Biomedical Literature Database were searched for related studies. A total of five studies including 2230 cases and 2229 controls were identified for the meta-analysis. The results indicate that TT genotype and T allele of miR-149 (rs2292832) are associated with significantly lower risks of IS in a homozygous model (OR = 0.70) and an allelic model (OR = 0.86). No significant associations were found between miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) and IS susceptibility in any of the studies. However, subgroup analysis by sample size indicates a significant decrease in risks of IS for CC genotype and C allele of miR-146a (rs2910164) in the large sample size group. Therefore, miR-149 (rs2292832) might be recommended as a predictor for IS risk, while miR-146a (rs2910164), miR-196a2 (rs11614913), miR-499 (3746444) are not.

Association between rs1801133 polymorphism and risk of adult ischemic stroke: Meta-analysis based on case–control studies

BackgroundThis study is aimed to quantify the strength of the association between rs1801133 polymorphism and ischemic stroke risk. MethodsWe have searched Medline, Springer, and Embase for studies investigating the association between rs1801133 polymorphism and ischemic stroke risk. We estimated the pooled odds ratio with its 95% confidence intervals to assess this possible association. ResultsForty case–control studies comprising 8809 cases and 9130 controls are eligible for this meta-analysis on the basis of relation of rs1801133 polymorphism to ischemic stroke risk. Hardy-Weinberg equilibrium was used to perform in controls for excluding articles. The overall analysis suggested that rs1801133 polymorphism was associated with increased risk of ischemic stroke (ORT versus C=1.16, 95% CI 1.10–1.22; ORTT versus TC+CC=1.32, 95% CI 1.18–1.47; ORTT+TC versus CC=1.11, 95% CI 1.04–1.18). Subgroup analysis showed that T allele was a significant strength between T allele and stroke risk in Asian, Caucasian, male and young-middle populations (OR=1.19, 1.11, 1.30, 1.16, respectively). Compared with TC+CC, TT genotype was found to be a risk factor for developing ischemic stroke in Asian, Caucasian and male (OR=1.41, 1.20, 1.77, respectively). Additionally, TT+TC retained a significant increase for ischemic stroke only in Asian comparable to CC genotype (OR=1.14). ConclusionsThe rs1801133 polymorphism could be capable of increasing ischemic stroke susceptibility in Asian, male and young-middle populations.

Tumor necrosis factor-alpha (− 308G/A, + 488G/A, − 857C/T and -1031 T/C) gene polymorphisms and risk of ischemic stroke in north Indian population: A hospital based case–control study

BackgroundGenetic factors may play a role in the susceptibility of Ischemic stroke (IS). Previous studies have shown that Tumour necrosis factor-α (TNF-α) gene polymorphisms were associated with the risk of IS in multiple ethnicities. The present case–control study tested the hypothesis that genetic polymorphisms of the TNF-α gene may affect the risk of IS in North Indian population. We investigated the association of four single nucleotide polymorphisms (−308G/A, +488G/A, −857C/T and -1031T/C) within TNF-α gene promoter and their haplotypes with the risk of IS. MethodsIS was classified using the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification. Genotyping was performed for 250 IS patients and 250 age- and sex-matched IS free controls by using SNaPshot technique. Multivariate logistic regression was used to control the confounding effects of demographic and risk factor variables. Haplotype analyses were done by using PHASE software and Linkage disequilibrium (LD) analyses were done by using Haploview version 4.2 software. ResultsAn independent association between TNF-α +488G/A (OR=2.59; 95%CI 1.46 to 4.60; p=0.001) and -857C/T (OR=1.77; 95%CI 1.01 to 3.11; p<0.04) and risk of IS was observed under dominant model. However, no significant association between -308G/A and -1031T/C gene polymorphisms and risk of IS was observed. Haplotype analysis showed that A308-G488-C857-T1031 haplotypes were significantly associated with the increased risk of IS [OR=1.66; 95%CI 1.02 to 2.71; p=0.003]. Strong linkage disequilibrium (LD) was observed for +488G/A and -857C/T (D’=0.41, r2=0.004). ConclusionsTwo SNPs (+488G/A and -857C/T) of TNF-α gene and their haplotypes are significantly associated with the risk of IS in the population enrolled from North India. Our findings indicate that polymorphisms and haplotypes of TNF-α gene may be used as a genetic marker for identifying individuals at increased risk for developing IS.

Impact of 5A/6A polymorphism of matrix metalloproteinase-3 on recurrent atherosclerotic ischemic stroke in Chinese

Little is known about the impact of the 5A/6A polymorphism of matrix metalloproteinase-3 (MMP-3) on recurrence of atherosclerotic ischemic stroke in Chinese. The aim of this study was to investigate the association of MMP-3 serum level and 5A/6A genetic polymorphism with the recurrence of atherosclerotic ischemic stroke in the Chinese Han population. We analyzed 106 large artery atherosclerosis (LAA) recurrent ischemic stroke patients and 545 LAA first onset ischemic stroke patients from January 2009 to June 2014. Serum MMP-3 concentrations were measured with an enzyme-linked immunosorbent assay. The genotypes of MMP-3 promoter polymorphism (−1171 5A/6A) were determined using polymerase chain reaction-restriction fragment length polymorphism. The frequencies of MMP-3 5A/6A+5A/5A (32.08% vs. 21.47%, p = 0.02) genotype and 5A (16.98% vs. 11.01%, p = 0.01) allele in the recurrent group was significantly higher than those in the first onset group. After adjustment for vascular risk factors, multivariate logistic regression analysis suggested that the MMP-3 5A/6A+5A/5A genotype was an independent risk factor for LAA recurrent ischemic stroke (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.09–2.79, p = 0.021). No significant difference was observed for the MMP-3 serum concentrations between the recurrent group and the first onset group (22.23 ± 8.31 vs. 21.49 ± 7.89 ng/ul, t = 0.88, p = 0.38). The MMP-3 (−1171 5A/6A) polymorphism may contribute to LAA recurrent ischemic stroke susceptibility. Analysis of 5A/6A polymorphism in MMP-3 may identify patients at higher risk for LAA ischemic stroke recurrence, who may be selected for intensive preventive therapy.

Association Between the Gene Polymorphisms of HDAC9 and the Risk of Atherosclerosis and Ischemic Stroke.

Genome-wide association studies have demonstrated various polymorphisms of histone deacetylase 9 (HDAC9) gene was strong risk locus for large-vessel stroke, but the results were controversial. This study aims to replicate the association between the previous detected SNPs of HDAC9 and the susceptibility of ischemic stroke. The study population consisted of 262 consecutive patients diagnosed with ischemic stroke and 300 age and gender matched unrelated controls between October 2012 and October 2014. Rs11984041, rs2389995, and rs2240419 of HDAC9 were genotyped and compared between the cases and controls. The SNP rs11984041 of HDAC9 was found nonpolymorphic in the population involved. The G allele of rs2389995 was found significantly associated with decreased risk of ischemic stroke, no matter with the codominant (AG v.s AA, 0.53 (0.36-0.77), P<0.001; GG v.s AA, 0.63 (0.27-1.43), P<0.001), dominant (AG+GG v.s AA, 0.54 (0.38-0.78), P<0.001), or the recessive model (GG vs AA+AG, 0.75 (0.33-1.71), P<0.001). On the other hand, The T allele of rs2240419 was found significantly associated with increased risk of ischemic stroke, no matter with the codominant (CT v.s CC, 1.75 (1.22-2.51), P<0.001; TT v.s CC, 2.67 (1.55-4.61), P<0.001), dominant (CT+TT v.s CC, 1.93 (1.38-2.71), P<0.001), or the recessive model (TT vs CC+CT, 2.07 (1.23-3.47), P<0.001). No linkage disequilibrium was found between rs2389995 and rs2240419 of HDAC9. In conclusion, the present study demonstrated the SNP rs11984041 of HDAC9 was nonpolymorphic in Chinese Han population. The minor G allele of rs2389995 significantly decreased and the minor T allele of rs2240419 significantly increased the risk of ischemic stroke.

Systematic Review by Multivariate Meta-analyses on the Possible Role of Tumor Necrosis Factor-α Gene Polymorphisms in Association with Ischemic Stroke.

A number of studies have investigated the association between tumor necrosis factor (TNF)-α gene polymorphisms and ischemic stroke susceptibility. However, results of different individual studies are often inconsistent. To provide a more robust evaluation of the association between polymorphisms of the TNF-α gene and ischemic stroke risk, we performed a systematic review with multivariate meta-analyses. PubMed, Embase, CNKI, and WanFang databases were searched up to December 20, 2014. Two reviewers independently extracted information and assessed quality of included studies after all the eligible studies were identified. Afterward, multivariate meta-analyses were performed using Stata 13. The estimation of polymorphisms and disease risk was presented by odds ratios (ORs) and corresponding 95 % confidence intervals (CIs). Forty-nine eligible case-control studies from 25 articles that explored the association between 10 TNF-α polymorphisms and ischemic stroke were indentified from aforementioned databases. The results of multivariate meta-analysis showed a significant association between -238G/A polymorphism (4760 patients and 4389 controls) and ischemic stroke risk in heterozygotes compared with wild genotype (AG vs. GG: OR 1.44, 95 % CI 1.11-1.87; AA vs. GG: OR 1.98, 95 % CI 0.73-5.40). No significant association of -308G/A, -857C/T, and -1031T/C polymorphisms was observed. The results of stratification analyses of -238G/A polymorphism showed that the AG genotype only increased the risk of ischemic stroke in Asians compared to GG genotype. No additional significant association was observed in this study. In conclusion, the present systematic review and meta-analysis support a prominent role of the TNF-α -238G/A polymorphism in the risk of ischemic stroke in Asian adults only, but do not support the role of -308G/A, -857C/T, -1031T/C, -244G/A, -367G/A, -646G/A, -806C/T, -863C/A, and +448G/A in the risk of ischemic stroke. The current evidence warrants further studies with high quality and large sample size to confirm.

Variants in the Atherogenic ALOX5AP, THBD, and KNG1 Genes Potentiate the Risk of Ischemic Stroke via a Genetic Main Effect and Epistatic Interactions in a Chinese Population

Ischemic stroke (IS) is a multifactorial disease that displays a strong genetic predisposition. However, the genetic architecture of IS has yet to be fully elucidated. It was hypothesized that epistasis between genes in multiple atherothrombotic pathways may play a vital role in determining the susceptibility to IS. The aim of the present study was to investigate the contributions of the hypothesized genetic factors to IS and the interactions between these genetic factors in a Chinese population. In this study, 351 cases with IS and 417 control subjects from a Chinese population were genotyped for single-nucleotide polymorphisms (SNPs) in 12 genes hypothesized to be involved in atherosclerosis, coagulation, and related pathways. We examined SNP main effects and epistatic interactions between these polymorphic loci. rs710446 of the KNG1 gene was associated with IS susceptibility based on an additive genetic model (rs710446: P = .012; odds ratio [OR], 1.247; 95% confidence interval [CI], 1.050-1.481) after adjusting for covariates. Furthermore, an epistatic interaction between the ALOX5AP, THBD, and KNG1 gene was also identified in association with stroke susceptibility (P < .001 after 1000 permutations). Based on the chi-squared test, the OR of the high-risk combination of the three-locus model increased the risk of IS by 2.53-fold (95% CI, 1.60-4.01; P < .0001). Our findings support the association of the epistatic interactions of ALOX5AP, THBD, and KNG1 and present novel evidence for the main effect of KNG1 gene on IS susceptibility, suggesting a modulation of stroke risk by a genetic main effect and gene-gene interactions.

Meta-Analysis of miR-146a Polymorphisms Association with Coronary Artery Diseases and Ischemic Stroke.

Coronary artery disease (CAD) and ischemic stroke (IS) are manifestations of atherosclerosis, with a high death rate. miR-146a is a microRNA that participates in the progress of CAD and IS. A single nucleotide polymorphism (SNP) in the precursor of miR-146a, rs2910164, was found to be associated with the risks of CAD and IS. However, the results were inconsistent and inconclusive. A meta-analysis was performed to assess the relationship of rs2910164 and CAD as well as IS susceptibility. The database Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM) were searched for related studies. Crude odds ratios with 95% confidence intervals were used to investigate the strength of the association by random- or fixed-effect model. A total of eight studies, with 3138 cases and 3097 controls were identified for the meta-analysis. The results shows that rs2910164 is associated with the risk of CAD significantly in allelic model (OR = 0.86), homozygous model (OR = 0.70), heterozygous model (OR = 0.80) and dominant model (OR = 0.76). The subjects carrying the GG genotype, GG + GC genotype or G allele are at lower risks of CAD. For the susceptibility of IS, there are no significant associations between rs2910164 and total studies. However, in subgroup analysis by sample size and ethnicity, the GG, GG + GC and G allele of rs2910164 are found to be associated with higher risks of IS in large sample size group and in Koreans, under homozygous and dominant models. In conclusion, the current meta-analysis suggests lower risks of CAD for GG, GG + GC genotype and G allele of rs2910164, while rs2910164 is not associated with the risk of IS. Thus rs2910164 might be recommended as a predictor for susceptibility of CAD, but not IS.

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 [β 0.16(0.01-0.30), P adj = 0.034] and recessive model [β 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.

Effect of the -148C/T, 448G/A, and -854G/A Polymorphisms of the β-Fibrinogen Gene on the Risk of Ischemic Stroke in Chinese Population

Several investigations have been performed to examine the influence of the β-fibrinogen (FGβ) gene polymorphisms on the risk of ischemic stroke, but the results of these studies are controversial. Our study aimed at investigating whether the FGβ gene (-148 C/T, 448 G/A, and -854 G/A) polymorphisms were associated with susceptibility to ischemic stroke by conducting meta-analysis. Relevant studies were identified from 4 Chinese databases, PUBMED and EMBASE before May 30, 2014. The strength of association was evaluated by the odds ratio with 95% confidence interval. Inconsistency index and the Cochran's Q statistic were used to check heterogeneity. Publication bias was tested using funnel plots and Egger's regression test. Thirty-two independent studies with 4311 cases and 4124 controls were included. Significant association between -148 C/T polymorphism and the risk of ischemic stroke was found in overall analysis and middle-age, but not in young adults and elderly people. Similarly, association was also observed for -854 G/A polymorphism, especially in cerebral arterial main trunk infarction (MCI) and cerebral penetrating arterial infarction (PCI). However, no significance was found between 448 G/A polymorphism and ischemic stroke in Chinese people; likewise, no evidence of a significant association was observed when stratified according to the subtype of ischemic stroke (MCI and PCI). These results suggest that -148 C/T and -854 G/A polymorphisms probably contribute to susceptibility of ischemic stroke.

Association of GWAS-Supported Variants rs2200733 and rs6843082 on Chromosome 4q25 with Ischemic Stroke in the Southern Chinese Han Population.

Genome-wide association studies (GWAS) have revealed two single-nucleotide polymorphisms (SNPs) on chromosome 4q25, rs2200733, and rs6843082, associated with ischemic stroke (IS) in Caucasians. However, subsequent validation studies have remained controversial. The current study aims to evaluate the associations between rs2200733, rs6843082, and IS in the southern Chinese Han population. A total of 1632 subjects were recruited in this case-control study. Genotyping for rs2200733 and rs6843082 was conducted in the Sequenom MassARRAY iPLEX platform. The genetic association of the rs2200733 and rs6843082 polymorphisms with IS was estimated using the PLINK program. Our results show that the SNP rs2200733 and rs6843082 have no significant associations with IS in additive, dominant, recessive, and allelic models (all p > 0.050). However, the results also indicate that the rs2200733 polymorphism is associated with systolic blood pressure (SBP) in IS patients in both the additive model (p adj = 0.002) and the recessive model (p adj = 0.002) after correcting for age. Meanwhile, the rs6843082 polymorphism showed a significant association with serum total cholesterol (TC) in IS individuals in the additive model (p adj = 0.017) and the dominant model (p adj = 0.023). These findings suggest that the SNP rs2200733 and rs6843082 on chromosome 4q25 may be not associated with IS susceptibility in southern Han Chinese. As for IS-related quantitative traits, the rs2200733 and rs6843082 polymorphisms might influence SBP and TC in IS patients, respectively.