angiotensinogen and Stroke

The association between ischemic stroke and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR; 677C>T and 1298A>C), endothelial nitric oxide synthase (eNOS; -786T>C, +894G>T, and variable number tandem repeat [VNTR]), phosphodiesterase 4D (PDE4D; SNPs 83 and 87), angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) 235M>T, paraoxonase 1 (PON1) 192Q>R, and apolipoprotein E (ApoE) ε2ε3ε4 remains inconclusive. Therefore, this updated meta-analysis aimed to clarify the presumed influence of genetic polymorphisms on ischemic stroke by meta-analyzing the comprehensive coverage of all individual association studies.. All case-control studies published in different languages such as English, Japanese, Korean, Spanish, Chinese, Hungarian, Ukrainian, or Russian were identified from databases. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via fixed- and random-effect models. Sensitivity analysis, heterogeneity test, Hardy Weinberg Equilibrium, and Egger's regression analyses were performed in this study.. A total of 490 case-control studies with 138,592 cases and 159,314 controls were included in this meta-analysis. Pooled ORs from all the genetic models indicated that MTHFR 677TT and 1298CC, eNOS +894TT and VNTR, PDE4D SNP 83, ACE DD, AGT 235TT, PON1 192RR, and ApoE ε4 polymorphisms were increasing the risks of ischemic stroke. Nevertheless, PDE4D SNP 87 and eNOS -786T>C polymorphisms are not associated with ischemic stroke risks.. Hence, the evidence from this meta-analysis concluded that MTHFR (677C>T and 1298A>C), eNOS (+894G>T and VNTR), PDE4D SNP 83, ACE I/D, AGT 235M>T, PON1 192Q>R, and ApoE ε2ε3ε4 polymorphisms predispose individuals to ischemic stroke.

Topics: Angiotensinogen; Apolipoproteins E; Aryldialkylphosphatase; Brain Ischemia; Case-Control Studies; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Stroke

The angiotensinogen (AGT) gene polymorphisms has been shown to be involved in the development of ischemic stroke. However, the published studies have yielded inconsistent results. We performed a meta-analysis to assess the correlation.. Published literature from PubMed, EMBASE, CNKI and Wanfang Data was searched. The association was assessed by odds ratio (OR) with 95% confidence intervals (CI). Publication bias was also calculated.. Eight studies (1636 cases and 1433 controls) on M235T polymorphism and four studies (726 cases and 495 controls) on T174M polymorphism were included in the meta-analysis. The results showed that M235T polymorphism was significantly associated with risk of ischemic stroke risk (TT vs. MM: OR=2.60, 95% CI=1.77-3.83; MT vs. MM: OR=1.37, 95% CI=1.01-1.86; TT+MT vs. MM: OR=0.43, 95% CI=0.35-0.54; MM+MT vs. TT: OR=1.74, 95% CI=1.31-2.32). There was also significant association between T174M polymorphism and ischemic stroke risk (MM vs. TT: OR=3.66, 95% CI=1.89-7.08; TT+MT vs. MM: OR=0.28, 95% CI=0.14-0.54). Further sensitivity analysis confirmed the significant association between AGT gene polymorphisms and risk of ischemic stroke. No evidence indicated publication bias.. The meta-analysis indicated the significant association of AGT gene polymorphisms (M235T, T174M) with risk of ischemic stroke in the Chinese population.

Topics: Angiotensinogen; Asian People; Brain Ischemia; Confidence Intervals; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Odds Ratio; Polymorphism, Single Nucleotide; Publication Bias; Stroke

Recently, the association between AGT M235T polymorphism and ischemic stroke (IS) has attracted widespread attention, and many investigations have been performed. However, the results were inconsistent. Therefore, we performed a meta-analysis to further evaluate the association between M235T and IS. All of the relevant studies were identified from PubMed, EMBASE, Chinese National Knowledge Infrastructure database (CNKI), Chinese Biological Medical Literature database (CBM), Chinese Wanfang and Chongqing VIP database up to January 2013. Statistical analyses were conducted with STATA software version 11.1. Odds ratios with 95% confidence interval were applied to evaluate the strength of the association. We performed the cumulative meta-analysis to assess the tendency of pooled OR over time. Heterogeneity was evaluated by Q-test and the I(2) statistic. The funnel plots and Egger's regression test were used to assess the publication bias. A significant association between AGT M235T polymorphism and IS was found under the dominant model (OR=1.368, 95% CI=1.070-1.749), recessive model (OR=1.66, 95% CI=1.310-2.103), over-dominant model (OR=1.285, 95% CI=1.085-1.523), co-dominant model (OR=1.574, 95% CI=1.276-1.942) and allele model (OR=1.447, 95% CI=1.207-1.735). Besides the Caucasian and the population-based controls, significant association could be found in the subgroup analysis of Asian and hospital-based controls. Results from cumulative analysis showed a tendency of significant association of this polymorphism with IS. However, the opposite trend was observed among Caucasians. Results from our meta-analysis indicated that the AGT M235T polymorphism might be a risk factor for IS among Asians, but not for Caucasians. More studies are required to further confirm our findings.

Topics: Angiotensinogen; Asian People; Databases, Factual; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Ischemia; Methionine; Stroke; Threonine; White People

Angiotensinogen (AGT) M235T and angiotensin-converting enzyme (ACE) Insertion/Deletion polymorphisms have been reported to be significantly associated with ischemic stroke. However, the results have been inconsistent. Therefore, we performed a comprehensive meta-analysis to evaluate the role of the AGT M235T and ACE I/D polymorphisms as risk factors for ischemic stroke in Han Chinese population.. We performed a comprehensive search in MEDLINE (PubMed), the China National Knowledge Infrastructure (CNKI) platforms and WANFANG databases, to identify the studies evaluating the association between the AGT M235T or ACE I/D polymorphisms and ischemic stroke, up to August 2011, in Chinese and English languages. The combined effects were estimated by fixed effects model or random effects model depending on the between-study heterogeneity, which was analyzed using the heterogeneity Q statistic test. Publication bias was evaluated using Begg's test, Egger's test and funnel plot.. A total of 58 studies were selected for the final meta-analysis, including 7168 ischemic stroke cases and 5944 controls. Among them, 11 studies evaluated the effect of AGT M235T as a risk factor for ischemic stroke, while the remaining evaluated the ACE I/D polymorphism. Overall, a significant association was identified for both the AGT M235T and ACE I/D polymorphisms, under pair wise comparisons, dominant, recessive and additive models, however, there was significant heterogeneity among the ACE I/D polymorphism studies (P<0.10). On meta-regression analyses, geographic region was identified as a significant source of between-study heterogeneity for both the polymorphisms. The stratified analysis by geographic distribution indicated that the AGT T allele could increase the risk of ischemic stroke in northern Chinese (OR=2.029, 95% CI: 1.714-2.401, P<0.001) as compared to southern Chinese individuals (OR=1.821, 95% CI: 1.586-2.090, P=0.002). In contrast, the ACE D allele could increase the susceptibility of ischemic stroke in southern Chinese (OR=1.692, 95% CI: 1.455-1.966, P<0.001) as compared to northern Chinese individuals (OR=1.297, 95% CI: 1.089-1.545, P=0.004). There was a possibility of publication bias for ACE I/D (P<0.001), but not for AGT M235T (P>0.05).. Our meta-analysis strongly suggested that the AGT M235T and ACE I/D polymorphisms significantly contribute to the risk of ischemic stroke in Han Chinese population. Also, the stratified analysis showed that the effects of these two polymorphisms differ by the geographic region. Further studies with more specific common information and large sample size are needed to understand the genetic mechanism of ischemic stroke.

Topics: Angiotensinogen; Asian People; China; Genetic Predisposition to Disease; Humans; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Publication Bias; Regression Analysis; Risk Factors; Stroke; Topography, Medical

The aim of this study was to investigate whether the M235T polymorphism in the angiotensinogen gene was associated with angiotensinogen levels, systolic and diastolic blood pressure, hypertension, and risk of ischemic cardiovascular disease in different ethnic populations.. One hundred twenty-seven studies published between January 1992 and March 2002 examining the association of angiotensinogen gene polymorphisms with the above-mentioned end points were selected. Pooled effect sizes and Mantel-Haenszel odds ratios were calculated using Review Manager. In white subjects, genotype was associated with a stepwise increase in plasma angiotensinogen levels of 5% (95% CI, 2% to 8%; P=0.0004) in MT heterozygotes and 11% (7% to 15%; P<0.00001) in TT homozygotes compared with MM individuals. Correspondingly, genotype was associated with a stepwise increase in aggregated odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) in MT individuals and 1.19 (1.10 to 1.30) in TT individuals in white subjects and of 1.29 (95% CI, 0.96 to 1.74) and 1.60 (1.19 to 2.15) in Asian subjects. M235T genotype did not predict systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group.. Angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects.

Topics: Angiotensinogen; Asian People; Black People; Blood Pressure; Genotype; Heterozygote; Homozygote; Humans; Hypertension; Myocardial Infarction; Myocardial Ischemia; Polymorphism, Genetic; Stroke; White People

Heart chymase rather than angiotensin (Ang)-converting enzyme has higher specificity for Ang I conversion into Ang II in humans. A new pathway for direct cardiac Ang II generation has been revealed through the demonstration that Ang-(1-12) is cleaved by chymase to generate Ang II directly. Herein, we address whether Ang-(1-12), chymase messenger RNA (mRNA), and activity levels can be differentiated in human atrial tissue from normal and diseased hearts and if these measures associate with various pathologic heart conditions.. Atrial appendages were collected from 11 nonfailing donor hearts and 111 patients undergoing heart surgery for the correction of valvular heart disease, resistant atrial fibrillation, or ischemic heart disease. Chymase mRNA was analyzed by real-time polymerase chain reaction and enzymatic activity by high-performance liquid chromatography using Ang-(1-12) as the substrate. Ang-(1-12) levels were determined by immunohistochemical staining.. Chymase gene transcripts, chymase activity, and immunoreactive Ang-(1-12) expression levels were higher in left atrial tissue compared with right atrial tissue, irrespective of cardiac disease. In addition, left atrial chymase mRNA expression was significantly higher in stroke versus nonstroke patients and in cardiac surgery patients who had a history of postoperative atrial fibrillation versus nonatrial fibrillation. Correlation analysis showed that left atrial chymase mRNA was positively related to left atrial enlargement, as determined by echocardiography.. As Ang-(1-12) expression and chymase gene transcripts and enzymatic activity levels were positively linked to left atrial size in patients with left ventricular heart disease, an important alternate Ang II forming pathway, via Ang-(1-12) and chymase, in maladaptive atrial and ventricular remodeling in humans is uncovered.

Topics: Aged; Angiotensinogen; Animals; Atrial Fibrillation; Chymases; Echocardiography; Female; Gene Expression Profiling; Heart Atria; Heart Valve Diseases; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; RNA, Messenger; Stroke; Ventricular Remodeling

The renin-angiotensin system (RAS) is a hormonal signaling mechanism implicated in the atherosclerosis and regulation of blood pressure. Angiotensin-converting enzyme (ACE) a key enzyme in the RAS, plays important roles in vascular remodeling atherosclerosis, and ischemic stroke. The aim of this study was to examine the possible contribution of the I/D in the ACE gene, M235T and T174M in the angiotensinogen (AGT) gene polymorphisms with ischemic stroke in young Mexican population.. A total of 224 patients with diagnosis of idiopathic ischemic stroke ≤45 years of age, and 224 controls matched by age and gender, were recruited from 2006 and 2016. The I/D, M235T and T174M polymorphisms were determined in all participants by PCR-RFLP.. There was a significant difference in the M235T genotype distribution (p = 0.01) and allele frequency between two groups (p = 0.01). Also, we found a significant difference in the T174M genotype distribution (p = 0.01) and the allele frequency between groups; (p = 0.02). In contrast, in I/D polymorphism, there was a similar genotype distribution; (p = 0.20) and allele distribution (p = 0.20). There were independent factors for ischemic stroke: M235T and T174M polymorphisms, smoking, hypertension, and familial history of atherothrombotic disease. The AGT levels were increased in the group of patients with stroke compared with the control group, but the AGT levels were not influenced by the allele or genotype in each polymorphism.. The M235T and T174M polymorphisms represented an increased risk for stroke in young Mexican individuals. In contrast, the I/D was not associated with in the same group of patients. The AGT levels were higher in the acute phase of stroke, but it was not determined by the polymorphisms.

Topics: Adult; Alleles; Angiotensinogen; Blood Pressure; Brain Ischemia; Case-Control Studies; Female; Gene Frequency; Genotype; Humans; Hypertension; Male; Mexico; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Renin-Angiotensin System; Risk Factors; Stroke

CADASIL is an inherited systemic small vessel disease, the affected status of brain vessels leading to subcortical vascular dementia. The defective gene is NOTCH3 in which over 230 different pathogenic mutations have been identified. The clinical course of CADASIL is highly variable even within families. Previous studies have shown that additional genetic factors modify the phenotype.. Altogether, 134 Finnish CADASIL patients with p.Arg133Cys mutation were analysed for possible associations between the apolipoprotein E (APOE) genotype, angiotensinogen (AGT) p.Met268Thr polymorphism or neutral p.Ala202Ala NOTCH3 polymorphism and earlier first-ever stroke or migraine.. We found no association between the APOE genotypes, AGT polymorphism, NOTCH3 polymorphism and earlier first-ever stroke or migraine.. The APOE, AGT and NOTCH3 polymorphism did not modify the onset of strokes or migraine in our CADASIL sample, which is one of the largest mutationally homogenous CADASIL populations published to date. International collaboration, pooled analyses and genomewide approaches are warranted to identify the genetic factors that modify the highly variable CADASIL phenotype.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Angiotensinogen; Apolipoproteins E; CADASIL; Female; Finland; Gene Frequency; Humans; Male; Middle Aged; Migraine Disorders; Mutation; Phenotype; Polymorphism, Single Nucleotide; Receptor, Notch3; Receptors, Notch; Stroke; Young Adult

To study the association of M235T (rs699) and T174M (rs4762) polymorphisms of the angiotensinogen (AGT) gene with the risk of cerebral stroke (CS) in the Russians of the Central Chernozem Region.. A total of 638 DNA samples obtained from 353 patients with CS and 285 sex- and age-matched healthy individuals were examined. The polymorphisms were genotyped by polymerase chain reaction (T174M) and TaqMan allelic discrimination (M235T) assays.. Heterozygous AGT 174TM genotype carriers were found to be at a higher risk for CS (odd ratio (OR) = 1.52; 95% confidence interval (CI), 1.08-2.15; p = 0.02). A gender-stratified analysis showed that the mutant 174M allele (OR = 1.86; 95% CI, 1.14-3.03, p = 0.01) and variant 174TM and 174MM genotypes (OR = 1.86; 95% CI, 1.09-3.20; p = 0.02) were associated with the higher risk of cerebral stroke in women.. The association of AGT T174M polymorphism with the risk of CS was first found; but the higher risk of the disease in the carriers of variant alleles and genotypes was observed in the women only.

Topics: Aged; Angiotensinogen; Female; Humans; Male; Middle Aged; Polymorphism, Genetic; Risk; Russia; Sex Factors; Stroke

To evaluate the associations of oral contraceptives (OC) exposure, angiotensinogen (AGT) gene polymorphism and joint effects on the risk of stroke in Chinese women.. On the basis of a prospective female cohort of contraceptive use, the first-ever-developed (FED) stroke cases, as well as, two sets of age-(± 3 years) and region-matched controls (including neighborhoods and hospitalized patients) were recruited. Between 1 July 2000 and 30 June 2009, a total of 453 FED stroke cases and 919 controls were recruited. Genotyping for polymorphisms of AGT gene was detected by Taqman method.. (1) The risk of stroke gradually increased with the cumulative time of OC use in women (P < 0.0001). Compared with the non-users, the risk of hemorrhagic stroke slightly increased among those with OC use (OR = 1.83, 95%CI: 1.25 - 2.66). (2) Women with AG/GG genotypes of A-6G locus or CA/AA genotypes of C11535A locus indicated that there was a slightly reduced risk of stroke (OR = 0.78, 95%CI: 0.61 - 0.99; OR = 0.73, 95%CI: 0.56 - 0.95). (3) Women with AA genotypes of A-20C locus and AG/GG genotypes of A-6G, when incorporated with CA/AA genotypes of C11535A locus with OC, it could increase the risk of hemorrhagic stroke (OR = 1.99, 95%CI: 1.34 - 2.97; OR = 1.84, 95%CI: 1.15 - 2.94; OR = 1.73, 95%CI: 1.06 - 2.85).. The AGT gene polymorphisms showed that they did have an impact on the risk of stroke. And the joint effect between women using OC and AGT gene polymorphisms could slightly increase the risk of stroke.

Topics: Aged; Angiotensinogen; Case-Control Studies; Contraceptives, Oral; Female; Genotype; Humans; Middle Aged; Risk Factors; Stroke

Angiotensin-converting enzyme 2 (ACE2) is a lately discovered enzyme catalyzing Angiotensin II into Angiotensin 1-7. Angiotensin II has been reported to impair endothelial progenitor cell (EPC) function and is detrimental to stroke. Here, we studied the role of ACE2 in regulating EPC function in vitro and in vivo. EPCs were cultured from human renin and angiotensinogen transgenic (R+A+) mice and their controls (R-A-). In in vitro experiments, EPCs were transduced with lentivirus-ACE2 or lentivirus-green fluorescence protein. The effects of ACE2 overexpression on EPC function and endothelial NO synthase (eNOS)/nicotinamide adenine dinucleotide phosphate oxidase (Nox) expression were determined. ACE2, eNOS, and Nox inhibitors were used for pathway validation. In in vivo studies, the therapeutic efficacy of EPCs overexpressing ACE2 was determined at day 7 after ischemic stroke induced by middle cerebral artery occlusion. We found that (1) lentivirus-ACE2 transduction resulted in a 4-fold increase of ACE2 expression in EPCs. This was accompanied with an increase in eNOS expression and NO production, and a decrease in Nox2 and -4 expression and reactive oxygen species production. (2) ACE2 overexpression improved the abilities of EPC migration and tube formation, which were impaired in R+A+ mice. These effects were inhibited by ACE2 or eNOS inhibitor and further enhanced by Nox inhibitor. (3) Transfusion of lentivirus-ACE2-primed EPCs reduced cerebral infarct volume and neurological deficits, and increased cerebral microvascular density and angiogenesis. Our data demonstrate that ACE2 improves EPC function, via regulating eNOS and Nox pathways, and enhances the efficacy of EPC-based therapy for ischemic stroke.

Topics: Acetophenones; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Cells, Cultured; Enzyme Inhibitors; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Peptides; Peptidyl-Dipeptidase A; Reactive Oxygen Species; Renin; Stem Cell Transplantation; Stroke; Transduction, Genetic

To clarify the effects of the association between combined oral contraceptives (COC) use and ACE/AGT gene on stroke risk, and to undertake a preliminarily study of the molecular mechanism of the association between COC exposure and predisposing genes of hypertension on the increased risk of stroke.. This study was a multi-center case-control study based on the population of 25 towns in the surveillance regions of Jiangsu province, China.. (i) The univariate analysis of the frequency of the DD genotype of ACE insert/delete (I/D) polymorphism between the cases and controls indicated its significant association with the stroke (P<0.01), especially for hemorrhagic stroke (P<0.01). (ii) Women with COC exposure and ACE I/D genotype had an increased risk for all strokes [adjusted odds ratio 5.63; 95% confidence interval (CI), 2.20, 15.68], and an increased risk for hemorrhagic stroke (adjusted odds ratio 31.53; 95% CI, 3.54, 281.14) after adjustment for education and occupation. (iii) Multivariate analyses showed that hypertension was the most important risk factor for hemorrhagic stroke and ischemic stroke. COC use was a significant risk factor for hemorrhagic stroke. The combined effects of COC use, for 15 years and above, and ACE I/D polymorphism increased the risk of all strokes by more than eight times, and the risk of hemorrhagic stroke by more than 15 times.. Hypertension was a most important risk factor for stroke incidence. The D allele of ACE I/D polymorphism may be a potential risk allele for stroke. COC users carried the ID+DD genotype that may further increase the risk of stroke, especially for hemorrhagic stroke.

Topics: Adult; Aged; Alleles; Angiotensinogen; Blood Pressure; Case-Control Studies; China; Contraceptives, Oral, Combined; Female; Genotype; Humans; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk; Risk Factors; Stroke

Pre-treatment with angiotensin receptor blockers is known to improve neurological outcome after stroke. This study investigated for the first time, whether the renin inhibitor aliskiren has similar neuroprotective effects.. Since aliskiren specifically blocks human renin, double transgenic rats expressing human renin and angiotensinogen genes were used. To achieve a systolic blood pressure of 150 or 130 mmHg animals were treated with aliskiren (7.5 or 12.5 mg/kg*d) or candesartan (1.5 or 10 mg/kg*d) via osmotic minipump starting five days before middle cerebral artery occlusion with reperfusion. Infarct size was determined by magnetic resonance imaging. mRNA of inflammatory marker genes was studied in different brain regions.. The mortality of 33.3% (7 of 21 animals) in the vehicle group was reduced to below 10% by treatment with candesartan or aliskiren (p<0.05). Aliskiren-treated animals had a better neurological outcome 7 days post-ischemia, compared to candesartan (Garcia scale: 9.9±0.7 vs. 7.3±0.7; p<0.05). The reduction of infarct size in the aliskiren group did not reach statistical significance compared to candesartan and vehicle (24 h post-ischemia: 314±81 vs. 377±70 and 403±70 mm(3) respectively). Only aliskiren was able to significantly reduce stroke-induced gene expression of CXC chemokine ligand 1, interleukin-6 and tumor necrosis factor-alpha in the ischemic core.. Head-to-head comparison suggests that treatment with aliskiren before and during cerebral ischemia is at least as effective as candesartan in double transgenic rats. The improved neurological outcome in the aliskiren group was blood pressure independent. Whether this effect is due to primary anti-inflammatory mechanisms has to be investigated further.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Brain Ischemia; Cerebral Arterial Diseases; Cerebrovascular Disorders; Chemokine CXCL1; Fumarates; Gene Expression; Humans; Interleukin-6; Rats; Renin; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Tetrazoles; Tumor Necrosis Factor-alpha

The association of renin C-4063T and angiotensinogen (AGT) T174M, AGT M235T and AGT A-6G polymorphisms with ischemic stroke of atherosclerotic etiology was investigated in 329 Tunisian patients with stroke and 444 controls.. Genotyping was performed using PCR-RFLP and the contributions of polymorphisms to the risk of stroke were analyzed using haplotype and multivariate regression analysis.. AGT 235T and AGT-6G allele and AGT 235T/T, AGT-6A/G and AGT-6G/G genotype frequencies were higher in patients. Linkage disequilibrium (LD) was noted for AGT174T with AGT235M and AGT(-6)A in patients, while AGT235M was in LD with AGT(-6)A in controls and AGT235T was in LD with AGT(-6)G in both groups. The AGT 174T/235T/-6A and AGT 174T/235M/-6G haplotypes were positively and negatively associated with stroke respectively. Multivariate regression analysis identified AGT 174T/235M/-6A, AGT 174T/235T/-6G, AGT 174T/235T/-6A and AGT 174M/235T/-6A haplotypes to be significantly associated with an increased risk of stroke.. Renin-angiotensin-aldosterone system polymorphisms influence the risk of atherosclerotic stroke in Tunisians.

Topics: Angiotensinogen; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Intracranial Arteriosclerosis; Linkage Disequilibrium; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Renin; Renin-Angiotensin System; Risk Factors; Stroke; Tunisia

The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease.. We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference.. We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke.. We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Carotid Artery Diseases; Cerebrovascular Disorders; Cohort Studies; Female; Genotype; Heterozygote; Humans; Hypertension; Male; Polymorphism, Genetic; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Stroke

Angiotensinogen is an essential component of the renin-angiotensin system. ACE-inhibitors and beta-blockers both have a direct influence on this system. To investigate whether the association between use of ACE-inhibitors or beta-blockers and the risk of myocardial infarction (MI) or stroke is modified by the T-allele of the angiotensinogen M235T polymorphism. In this study, 4097 subjects with hypertension , aged 55 years and older, were included from the Rotterdam Study, a population-based prospective cohort study in The Netherlands, from July 1, 1991 onwards. Follow-up ended at the diagnosis date of MI, stroke, death, or the end of the study period (January 1, 2002). The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model with adjustments for each drug class as time-dependent covariates. The risk of MI was increased in current use of ACE-inhibitors with the MT or TT genotype compared to ACE-inhibitors with the MM genotype (Synergy Index (SI): 4.00; 95% CI: 1.32-12.11). A significant drug-gene interaction was not found on the risk of stroke (SI: 1.83; 95% CI: 0.95-3.54) in ACE-inhibitor users or between current use of beta-blockers and the AGT M235T polymorphism on the risk of MI or stroke. ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Cohort Studies; Comorbidity; Female; Genetic Predisposition to Disease; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Netherlands; Pharmacogenetics; Polymorphism, Genetic; Prospective Studies; Renin-Angiotensin System; Risk Factors; Stroke

While gene polymorphism for angiotensinogen (AGT) is reported to contribute to the regulation of blood pressure and salt sensitivity, its effect on the risk of ischemic stroke remains controversial. We hypothesized that polymorphism of the AGT gene could be a risk factor for ischemic stroke. Major clinical risk factors and the AGT gene M235T polymorphism were examined in 147 consecutive stroke patients and 133 healthy age-matched controls. All patients were categorized into four stroke types (single lacuna, multiple lacunae, large-artery atherosclerosis and branch atheromatous disease in brainstem) and two vascular groups (large and perforating arterial lesions). The AGT gene M allele significantly increased the risk of single lacuna, multiple lacunae and small arterial lesions, in male patients (p=0.029, 0.031 and 0.026, respectively). Synergistic effects of the AGT gene polymorphism and clinical risks were not observed. In conclusion, AGT M allele may present a risk of lacunar infarctions in Japanese men, independent of hypertension.

Topics: Aged; Aged, 80 and over; Angiotensinogen; Asian People; Brain; Brain Infarction; Brain Ischemia; Cerebral Arteries; DNA Mutational Analysis; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Humans; Intracranial Arteriosclerosis; Japan; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Sex Characteristics; Sex Factors; Stroke

Hypertension is the most common risk factor for hemorrhagic stroke. An experimental model of stroke, the stroke-prone spontaneously hypertensive rat (SHRSP), which has been enormously useful in studies of cerebral circulation, has been used in >1000 papers. However, SHRSP usually have an ischemic or less commonly hemorrhagic stroke in the cortex, not in the brain stem, cerebellum, or basal ganglia, as in patients with hypertension. The goal of this study was to develop a model of hemorrhagic stroke in hypertensive mice.. A genetic model of hypertensive mice, double transgenic mice (R+/A+) that overexpress both human renin (R+) and human angiotensinogen (A+), and nonhypertensive control mice were divided into 3 groups: (1) high-salt diet; (2) Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthases, in drinking water; and (3) high-salt diet and L-NAME.. All R+/A+ mice on high-salt diet and L-NAME died within 10 weeks, with hemorrhage in the brain stem, and several of the mice had hemorrhages in brain stem, cerebellum, and basal ganglia. No control mice on high-salt diet and L-NAME had hemorrhagic stroke. Arterial pressure in R+/A+ mice increased progressively during high-salt diet and L-NAME. In R+/A+ and control mice, high-salt diet or L-NAME alone did not increase arterial pressure.. We now describe the first model of spontaneous hemorrhagic strokes in hypertensive mice. The type and locations of stroke are reasonably similar to those observed in patients with hypertension.

Topics: Angiotensinogen; Animal Feed; Animals; Blood Pressure; Brain; Circadian Rhythm; Disease Models, Animal; Female; Humans; Hypertension; Intracranial Hemorrhages; Mice; Mice, Transgenic; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Renin; Salts; Stroke

Lacunar infarction is a unique stroke entity with characteristic symptoms. However, it is often silent clinically. The possible genetic predisposition to symptoms of lacunar infarction was investigated.. One-hundred and fifty-one patients with lacunar stroke were consecutively recruited. Lacunar stroke was diagnosed based on both neurological symptoms and lacunar lesion(s), demonstrated by MRI, that were responsible for the symptoms. One-hundred and fifty control subjects with MRI-proven lacunar lesions without neurological symptoms served as controls. There was no significant difference in age, sex and prevalence of known risk factors between cases and controls. Insertion and deletion polymorphisms of the angiotensin-converting enzyme gene (ACE), M235T substitution of the angiotensinogen gene (AGT), and A1133C substitution of type 1 receptor of the angiotensin II gene were determined.. The frequency of ACE D allele was significantly higher in symptomatic patients compared with asymptomatic subjects (0.44 vs. 0.36, p < 0.05). The genotype distribution of AGT was significantly different between symptomatic and asymptomatic patients (chi(2) = 6.6, p = 0.037). Multiple logistic regression analysis revealed that ACE gene and AGT genotypes were independently associated with the neurological manifestation of lacunar infarction. In subjects with 1 lacuna, the odds ratio of the ACE DD genotype for symptomatic manifestation was 4.98 (95% CI 1.25-19.9). In subjects with 4 or more lacunae, the odds ratio of the ACE II genotype for symptomatic manifestation was 0.24 (95% CI 0.10-0.56). Furthermore, the ACE gene polymorphism was significantly different between symptomatic patients with a single lacuna and asymptomatic subjects with 4 or more multiple lacunar infarctions (chi(2) = 10.6, p = 0.005).. These findings suggest that 2 subtypes of lacunar infarction, single symptomatic lacuna and multiple asymptomatic lacunae, may possess different genetic backgrounds. Subjects with the ACE DD genotype could be more predisposed to be symptomatic in first-ever lacunar stroke, while the ACE II genotype may convey resistance to symptoms even after multiple lacunar strokes. Polymorphism of genes of the renin-angiotensin system could be involved in the manifestation of neurological symptoms of lacunar infarction.

Topics: Age Factors; Aged; Alleles; Angiotensinogen; Angiotensins; Case-Control Studies; Cerebral Infarction; Female; Gene Frequency; Genotype; Humans; Magnetic Resonance Imaging; Male; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Sex Factors; Stroke

Topics: Adolescent; Anemia, Sickle Cell; Angiotensinogen; Child; Child, Preschool; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic; Stroke

The ThrThr genotype of the angiotensinogen (AGT) Met235Thr polymorphism has been associated with elevated AGT levels, hypertension, increased heart disease risk, and improved blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitors. We hypothesized that risk of stroke or myocardial infarction (MI) associated with ACE inhibitor use varies by AGT genotype, with a larger protective effect of ACE inhibitors in individuals with the ThrThr genotype than individuals who are carriers of the Met allele.. We conducted a population-based case-control study. Participants were health maintenance organization members aged 30 to 79 years with treated hypertension. Those who survived incident stroke (n = 116) or MI (n = 208) during the study period were designated as cases. Control subjects (n = 717) were randomly sampled and frequency-matched to MI cases on age, sex, and calendar year. Health history, medication use, and AGT genotype were assessed.. ThrThr genotype was present in 21% of stroke cases, 26% of MI cases, and 19% of control subjects. Compared with nonuse, ACE inhibitor use was associated with lower stroke risk among Thr homozygotes (odds ratio [OR] = 0.37, 95% CI = 0.14 to 0.99) than among Met carriers (OR = 1.4, 95% CI = 0.88 to 2.4; P for interaction =.02). Compared with nonuse, ACE inhibitor use was associated with similar MI risk among Thr homozygotes (OR = 0.90, 95% CI = 0.62 to 1.3) and among Met carriers (OR = 1.2, 95% CI = 0.60 to 2.5; P for interaction = 0.5).. In this hypertensive population, the association of ACE inhibitor use with risk of nonfatal stroke varied by genotype. The protective association between ACE inhibitor use and nonfatal stroke risk among individuals with ThrThr genotype was not observed for nonfatal MI.

Topics: Adult; Aged; Alleles; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Case-Control Studies; Female; Genotype; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Risk; Stroke

Stroke is one of the most devastating complications of patients with sickle cell disease (SCD). Currently, there are no known molecular or genetic markers that can be used to assess the risk of stroke in this population. We have previously shown that relative hypertension may be one risk factor for stroke in SCD. In a case-control study, we investigated the association between GT-repeat polymorphism within the angiotensinogen (AGT) gene and the risk of stroke in pediatric patients with SCD. After informed consent was obtained, 63 patients (21 stroke subjects and 42 nonstroke control subjects matched according to age and sex) with SCD followed at local pediatric hematology clinics were genotyped to test the association of specific GT-repeat alleles of the AGT gene and occurrence of stroke. There were statistical differences in the distribution of the genotypes among stroke and nonstroke SCD patients (chi(2) = 10.82, df = 11, P < 0.05). We also found GT-repeat alleles A3 and/or A4 of the AGT gene conferred a four-fold increase in the risk of stroke (odds ratio [OR] = 4, P < 0.05). The attributable odds ratio for allele A3 and A4 is 2.24 and 4.33, respectively (P < 0.005). Our results suggest that GT-repeat within the AGT gene may be associated with risk of stroke in pediatric SCD. The relative risk of stroke in the presence of alleles A3 and/or A4 is fourfold greater than in the absence of these alleles. If these data are substantiated in a larger cohort of patients, our results indicate that the determination of GT-repeat of AGT gene may be a useful genetic marker to assess the risk for stroke of patients with SCD. Am. J. Hematol. 68:164-169, 2001. Published 2001 Wiley-Liss, Inc.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Angiotensinogen; Case-Control Studies; Child; Child, Preschool; Dinucleotide Repeats; Female; Gene Frequency; Genetic Markers; Humans; Male; Odds Ratio; Polymorphism, Genetic; Risk Factors; Serine Proteinase Inhibitors; Stroke

To evaluate the association between hypertensive cerebrovascular stroke and renin-angiotensin system gene polymorphism from Chinese cohort.. The polymorphisms of angiotensinogen(AGT) and angiotensin-converting enzyme(ACE) from 257 cases of simple essential hypertension(EH) and 218 cases of hypertensive stroke(131 hemorrhagic cases and 87 ischemic cases were detected by PCR-RFLP.. The frequencies of DD genotype and D allele of ACE gene in ischemic stroke were significantly higher than those in hemorrhagic stroke and EH, and the odds ratios(OR) of DD/II genotype were 3.25(2.20-4.79) and 2.87(2.03-4.06), while the OR of D/I allele were 1.83(1.38-2.43) and 1.69(1.27-2.24) respectively. Otherwise, there was no difference in frequency distribution of Met235Thr mutation polymorphism and DD+TT/non DD non TT combined among the three groups.. The I/D polymorphism of ACE gene may be one of the risk factors and susceptible genetic markers for ischemic stroke with essential hypertension in Chinese.

Topics: Angiotensinogen; Genotype; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Stroke