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Deletion Polymorphism in the Angiotensin-Converting Enzyme Gene in Patients With a History of Ischemic Stroke
Abstract
We evaluated the genotypes of the angiotensin-converting enzyme (ACE) gene in 101 subjects with and 109 subjects without a history of ischemic stroke. All were attending a metabolic ward. The two groups were compared for major risk factors for ischemic events. Genotypes were determined by polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Deletion polymorphism of the ACE gene (DD genotype) was shown to be more common in subjects with a history of stroke than in those without (relative risk, 1.76; confidence intervals, 1.02 to 3.05). A positive family history for ischemic complications of atherosclerosis was also more common in subjects with documented events (relative risk, 1.99; confidence intervals, 1.10 to 3.59). DD genotype and a positive family history were strong independent discriminators of cerebral ischemia. Plasma levels of tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor-1 help identify subjects with a history of cerebral ischemic episodes. When such fibrinolytic variables were included in the analysis, the DD genotype still strongly and independently discriminated subjects with a stroke history and significantly interacted with TPA levels > 10 ng/mL in such identification. We conclude that in subjects attending a metabolic ward, homozygosity for a deletion polymorphism of the ACE gene consistently discriminates subjects with a stroke history. Interaction with TPA improves such identification.
... The polymerase chain reaction (PCR) technique, speci®c primers and experimental conditions employed for the ACE genotyping were those suggested by Rigat et al. [39] with subsequent modi®cations [40]. The ampli®cation products were resolved in a 2% agarose gel by a 40 mmol/l tris-acetate buffer pH 7.7 containing 1 mmol/l EDTA, stained with 0.5 mg/ml of ethidium bromide, and visualised by UV light. ...
... In accordance with this ®nding, allele frequencies showed no signi®cant differences among the three groups. In all groups there was a higher representation of the D allele, which is in agreement with a previous study, in subjects from the Mediterranean regions [40]. When we analysed our data separately for Italian and UK patients, the frequency of the DD genotype was 52% for the Italian and 26% for the UK patients respectively, similar to that reported by other authors in these populations [40,42]. ...
... In all groups there was a higher representation of the D allele, which is in agreement with a previous study, in subjects from the Mediterranean regions [40]. When we analysed our data separately for Italian and UK patients, the frequency of the DD genotype was 52% for the Italian and 26% for the UK patients respectively, similar to that reported by other authors in these populations [40,42]. The higher frequency of the DD genotype in the whole group of patients was brought about by the overrepresentation of Italian patients in our study. ...
Genetic factors are involved in the development of diabetic nephropathy in Type 1 diabetes. We have examined the association of four candidate genes, angiotensin converting enzyme (ACE): insertion/deletion (I/D) polymorphism, plasminogen activator inhibitor-1 (PAI-1): 4G/5G polymorphism, decorin: 179/183/185 polymorphism and Werner syndrome helicase: C/R polymorphism, with the presence of diabetic nephropathy in Type 1 diabetic patients.
175 Type 1 diabetic patients with albuminuria (59 with microalbuminuria and 116 with macroalbuminuria) were compared with 136 Type 1 diabetic patients with normoalbuminuria and duration of disease longer than 15 years (mean+/-SD: 25+/-8 years). 200 non-diabetic subjects were also studied as background population.
We found no association in the polymorphism of the four genes examined between patients with and without diabetic nephropathy and the control subjects.
The genes studied are unlikely to be involved in the susceptibility to nephropathy in Type 1 diabetic patients.
... This ethnic difference in response to hypertension drug therapy may be due to the lower renin activity and prostaglandin levels found in the black population [3,25]. Genetic deletion/insertion polymorphisms of the ACE gene have been associated with increased risk for myocardial infarction and cerebral stroke [19,66,89,98]. Increased ACE activity levels (1.7-fold) were reported in patients homozygous for the D allele (i.e. ...
... DD) [89]. Margaglione et al. demonstrated that patients with this gene polymorphism (DD) displayed almost twice the risk for cerebral stroke than those without this gene deletion [66]. ...
Stroke is the leading cause of long-term disability in the United States and affects more people than any other neurologic disorder. Hypertension is a major risk factor associated with stroke. Several anti-hypertensive agents have been used to treat chronic hypertension to reduce the morbidity and mortality of stroke. Previous experimental studies have shown reduced stroke mortality with angiotensin-converting enzyme (ACE) inhibitors. This review discusses the development of stroke and potential use of ACE inhibitors in prevention and treatment of this disease. Furthermore, this review focuses on current investigations aimed at cellular mechanisms involved in stroke-induced microvascular alterations.
... The PCR technique, primers, and experimental conditions employed for the ACE genotyping were the ones suggested by Rigat et al 29 with some modifications. 30 The amplification products were resolved in 2% agarose gels with a 40 mmol/L Tris-acetate buffer, pH 7.7, containing 1 mmol/L EDTA, stained with 0.5 g/mL of ethidium bromide, and visualized by UV light. ...
... Genotype frequencies of the PAI-1 gene 4G/5G polymorphism in the whole sample were . 26 25,30 and in other white populations 16 -18,33 and did not differ from those predicted by Hardy-Weinberg equilibrium. When stratified according to some variables (Table 2), mean plasma levels of PAI-1 antigen were higher in men, hypertensives, alcohol drinkers, cigarette smokers, and PAI-1 4G/4G homozygotes. ...
Plasminogen activator inhibitor-1 (PAI-1) plasma levels have been consistently related to a polymorphism (4G/5G) of the PAI-1 gene. The renin-angiotensin pathway plays a role in the regulation of PAI-1 plasma levels. An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been related to plasma and cellular ACE levels. In 1032 employees (446 men and 586 women; 22 to 66 years old) of a hospital in southern Italy, we investigated the association between PAI-1 4G/5G and the ACE I/D gene variants and plasma PAI-1 antigen levels. None of the individuals enrolled had clinical evidence of atherosclerosis. In univariate analysis, PAI-1 levels were significantly higher in men (P<.001), alcohol drinkers (P<.001), smokers (P=.009), and homozygotes for the PAI-1 gene deletion allele (4G/4G) (P=.012). Multivariate analysis documented the independent effect on PAI-1 plasma levels of body mass index (P<.001), triglycerides (P<.001), sex (P<.001), PAI-1 4G/5G polymorphism (P=.019), smoking habit (P=.041), and ACE I/D genotype (P=.042). Thus, in addition to the markers of insulin resistance and smoking habit, gene variants of PAI-1 and ACE account for a significant portion of the between-individual variability of circulating PAI-1 antigen concentrations in a general population without clinical evidence of atherosclerosis.
... 20 Polymerase chain reaction (PCR) techniques, primers, and experimental conditions employed for ACE genotyping were the ones suggested by Rigat et al, 21 with some modifications. 22 PCR assays were carried out on 50-Lvolume samples in a Perkin Elmer-Cetus thermal cycler. Each sample contained 0.5 g of genomic DNA, 15 pmol of each primer, and 1 U of thermostable Taq polymerase. ...
... Genotype frequencies of the PAI-1 4G/5G, ACE I/D, and fibrinogen B-chain G3 A Ϫ455 gene polymorphisms and the allele frequencies calculated were similar to those observed in samples from the same region 15,[22][23][24] ...
The relevance of elevated levels of C-reactive protein (CRP) in cardiovascular disease is gaining increasing recognition. A family history of coronary artery disease is a major determinant of coronary artery disease in the offspring. In a cohort of 1048 individuals without clinical evidence of atherosclerosis, we investigated the relationships between CRP levels and a family history of myocardial infarction. We measured CRP, fibrinogen, plasminogen activator inhibitor-1, total cholesterol, triglycerides, and some genetic polymorphisms: plasminogen activator inhibitor-1 (4G/5G), fibrinogen (Bbeta-chain G-->A(-455)), and angiotensin-converting enzyme insertion/deletion (I/D). Clinical data were collected by a World Health Organization-modified questionnaire for cardiovascular disease. When compared with subjects without first-degree relatives who had suffered a myocardial infarction (n=867), subjects with such first-degree relatives (n=181) were older (P=0.001), more often hypertensive (P<0. 001), and homozygous for the 4G allele (4G/4G) of the plasminogen activator inhibitor-1 gene (P=0.003). In addition, they had a higher body mass index (P=0.036), raised plasma fibrinogen (P<0.007) and total cholesterol (P<0.001) concentrations, and CRP levels >0.33 mg/L (P=0.005). In a multiple logistic regression analysis, age (odds ratio [OR] 1.03, 95% confidence interval [95% CI] 1.01 to 1. 05), total cholesterol (OR 1.35, 95% CI 1.11 to 1.65), plasminogen activator inhibitor-1 4G/4G (OR 1.72, 95% CI 1.20 to 2.45), and CRP levels >0.33 mg/L (OR 1.75, 95% CI 1.05 to 2.91) were all independently associated with a positive family history of myocardial infarction. We therefore conclude that raised levels of CRP independently identify the offspring of patients with a myocardial infarction.
... Markus et al reported a strong association between lacunar infarction CVD and ACE gene deletion polymorphism [9]. Other studies have demonstrated a ORIGINAL ARTICLES strongly significant association between ACE gene deletion polymorphism and ischemic CVD in white [10,11] and Japanese populations [12,13]. In contrast, the studies of Catto et al [14] and Agerholm-Larsen et al [15] in a white population found no difference in the prevalence of deletion polymorphism of the ACE gene between CVD patients and control subjects. ...
... In previous studies involving white and Japanese populations [9][10][11][12][13][14][15], results often showed that deletion polymorphism of the ACE gene might play an important role in the pathogenesis of CVD, despite widely different results (Table 4). A recent meta-analysis of data on the ACE gene in ischemic stroke revealed that the D allele is a modest but independent risk factor for ischemic stroke [34]. ...
Angiotensin I-converting enzyme (ACE) gene deletion polymorphism (D) has recently been suggested as a significant risk factor for cerebrovascular disease in studies involving Japanese and white populations. We investigated the role of ACE D polymorphism in the pathogenesis of cerebrovascular disease in Taiwanese.
To examine the association of ACE genotype and allele frequency with cerebrovascular disease, we conducted a study of 306 stroke patients and 300 control subjects matched by age and sex.
Although the frequencies of both the homozygous deletion (DD) genotype and the D allele were greater in stroke patients than in control subjects, these differences were not significant. Further comparison of the frequencies of the DD genotype and the D allele in the three stroke subgroups (intracerebral hemorrhage, probable large-vessel disease, and probable small-vessel lacunar infarction) with the control group revealed no significant associations. Moreover, ACE gene polymorphism was not significantly associated with age of onset of stroke. Stepwise logistic regression analysis of the presence of the D allele and data on risk factors confirmed the lack of significant association between ACE deletion polymorphism and cerebrovascular disease. Moreover, no association was identified between ACE genotypes and any of the relative risk factors for cerebral infarction or severity of carotid atherosclerosis.
Our results suggest that deletion polymorphism of the ACE gene is not associated with the pathogenesis of cerebrovascular disease in Taiwanese.
... Nei pazienti ipertesi, il fattore VWF è stato associato con ACE-DD (49,50), che media lo stress ossidativi ed è associato con la disfunzione endoteliale (51). La relazione tra ACE-DD genotipo, le lesioni ischemiche e le patologie cardiovascolari è controverso (52)(53)(54)(55)(56), anche se questa era stata associata agli infarti lacunari in assenza di ateromasia delle carotidi e a leucoaraiosi (57). Il polimorfismo ACE-DD era stato associato all'emicrania con (58) e senza aura (59), lo stesso era associato ad un incremento in frequenza degli attacchi (59). ...
Over the last decades clinical studies have demonstrated an association between migraine, particularly with aura, and ischaemic stroke. The pathophysiological mechanism involved in migraine and ischaemic stroke interaction is complex and unknown. An endothelial disfunction may be a possible cause or the consequence of the migraine and it would be able to explain the presence of the association between migraine and ischaemic stroke. Triptans represents the drugs widely used in the acute management of the migraine. Since they has been introduced in the early 1990s, triptans are generally proven to be safe and well tolerated, even if it are contraindicated in patients with both vascular risk or cerebrovascular syndromes. In the future, a best understanding of the mechanisms involved in the development of ischaemic stroke in patient with migraine could be useful in order both to determine the therapeutic strategies and to prevent the ischaemic stroke.
... In line with the linkage to PDE4D [81,82], polymorphisms in this gene are associated with increased stroke risk [83,84]. Another well-studied gene is angiotensinogenconverting enzyme (ACE) (involved in hypertension), in which an insertion/deletion polymorphism has been associated with ischemic stroke in some studies [85,86], although others have not been successful in replicating these findings [87]. Notably, in a study including TOAST subtyping, this association only persisted for lacunar infarctions [88], while another study was unable to detect such an association [89]. ...
... Furthermore, there is a growing and continuing interest in the link between a variant deletion of the gene for ACE and an increased incidence of myocardial infarction 1,2 . Many studies have reported an association between the ACE-D allele and both coronary heart disease [3][4][5] and stroke 6,7 , although other studies have failed to confirm this result 2 . The mechanism underlying this positive association is not yet clear. ...
Background:
An increasing number of studies with conflicting results regarding the association between angiotensin-converting enzyme (ACE) gene deletion polymorphism and cardiovascular disease has recently been published. The present prospective long-term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects over 6 years of follow-up. We also investigated the effects of the ACE-I/D genotypes on diastolic function by echocardiography in healthy subjects without any risk factors and any events after 6 years of follow-up.
Methods:
Population:
684 healthy volunteers (aged 25-55 years) normotensive and free of cardiovascular diseases, with acceptable echocardiographic window were enrolled. All subjects had to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at entry. All subjects have undergone a complete physical examination, 12-lead ECG and ECHO; DNA analysis and serum cholesterol have been performed on venous blood samples. All subjects underwent a clinical evaluation each year for the 6-year duration of the study. In addition, 275 subjects without any risk factors underwent an ECHO every year of the follow-up, to check the influence of genotypes on myocardial diastolic performances.
Results:
All 684 subjects completed 6 years of follow-up. We obtained 3 genetically distinct groups: I) the ACE-DD group (n = 225, 80 F/ 145 M, mean age 43.4 +/- 7.6 years) with 42 hypertensive subjects (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary syndromes (ACS). There was no association between family history, smoking habit, hypercholesterolaemia and events. 2) the ACE-ID group (n = 335, 116 F/2 19 M, mean age 43.6 +/- 7 years) with 16 hypertensive subjects (4.7%) and 3 subjects with ACS. 3) the ACE-II group (n = 124, 45 F/79 M, mean age 42.5 +/- 6.9 years) with 2 hypertensive subjects (1.6%) and I HF subject. The incidence of hypertension and cardiovascular events, was significantly higher in the ACE-DD (53 cases, 23%) than in the ACE-ID and ACE-II groups (20 and 3 cases, 5.9% and 2.4%, respectively), p = 0.0001. The higher incidence of hypertension was observed in the older age groups (36-45 and 46-55 years) with ACE-DD and ACE-ID genotypes. Moreover, ACE-DD significantly and early affected myocardial diastolic properties in the total group examined, also when stratified for age. There was a reduction of E/A ratio and it was more evident in subjects aged 36-45 and 46-55 years, p = 0.0001.
Conclusion:
Our data suggest that ACE-DD polymorphism is associated with a higher incidence of hypertension in baseline healthy subjects, irrespective of other risk factors, and appears to affect the diastolic function. These effects were apparent predominantly in the older age groups.
... On the other hand, infusion of angiotensin II results in an in vivo substantial incre a s e in the circulating levels of plasminogen activator inhib i t o r-1. ACE also inactivates bradykinin, a vasodilator and natriuretic substance 21 . ...
Stroke is a multifactorial disease in which genetic factors play an important role. This study was carried out to determine angiotensin-converting enzyme (ACE) gene polymorphism in Turkish acute stroke patients and to establish whether there is an association of angiotensin-converting enzyme gene I/D polymorphism with clinical parameters. In this study 185 patients and 50 controls were recruited. We have investigated the association among the allelic distribution of the insertion/deletion (I/D) polymorphism of the ACE gene identified by polymerase chain reaction. Distribution of ACE gene I/D genotypes and allele frequencies in patients were not significantly different from controls. D allele frequencies were 57.8% in patients versus 53.0% in controls and I allele 42.2% versus 47% respectively. History of hypertension, stroke, renal, heart and vessel diseases incidence and age, gender, systolic-diastolic blood pressures and creatinine levels were significantly high in patients. But these results and ACE activities had no significant differences among the ACE genotypes in patients and controls. Our results suggest that the ACE gene polymorphism is not associated with the pathogenesis of stroke in Turkish stroke patients.
... The high ACE D allele carrier rate among Saudi subjects (93.2%) was relatively similar to that reported among Egyptians, 94.6%; 18 Chinese, 91.6%; 62 and Japanese, 89.4%. 63 However, it is somewhat higher than that among Italians, 84.4%; 64 Iranians, 81.4%; 65 Indians, 70.7%; 66 British, 72.6%; 67 Japanese, 67.2%; 68 and Malaysians, 61.8%. 69 As a conclusion, this study showed that the Saudi population has a peculiar pattern regarding the frequency of thrombophilic mutations in the form of low a carriage rate of FVL and FII mutations, intermediate one for PAI-1 and MTHFR mutations but very high ACE D allele carriage rate (Figs. ...
Thrombophilic mutations increase the tendency toward thromboembolic disease. The aim of this study was to estimate the prevalence of the genetic variants related to thrombophilia among Saudis compared with other populations. Real-time polymerase chain reaction (PCR) genotyping was carried out to determine the polymorphic variants of factor V Leiden 1695G/A, prothrombin 20210G/A, plasmin activator inhibitor 1 4G/5G, methylene tetrahydrofolate reductase (MTHFR) 677C/T, MTHFR 1298A/C, and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) among a representative sample of healthy Saudi subjects. Carraige rate for each of the mutant variants of factor V Leiden (FVL) and FII genes constituted 2% of the surveyed subjects giving an allele frequency of 0.01, homozygous forms of plasminogen activator inhibitor-1 (PAI-1) gene 4G/4G, MTHFR 677TT, 1298CC, and ACE DD were present among 7.7, 2.55, 7, and 51.8% of subjects with a mutant allele frequency of 0.4, 0.19, 0.29, and 0.73, respectively. This study showed that the Saudi population has a peculiar pattern regarding thrombophilic mutations that might warrant additional considerations for prophylaxis.
... The findings here reveal that individuals with ACE I/I homozygote tend to have lower ACE plasma level, thereby making them less likely to be associated with cerebral infarction [24][25][26] or other cardiovascular disorder like hypertension [27,28] thus increasing risk for AD [29,30]. These susceptibilities imply that the possible effects of ACE inhibitors in the treatment of AD may be varied, depending on the ACE genotypes of AD patient. ...
angiotensin-converting enzyme (ACE) gene insertion/deletion (indel) polymorphism is considered a biomarker for Alzheimer's disease (AD). However, the associations of ACE gene and protein level to AD are undetermined among Taiwanese.
this study investigated 257 Taiwanese cases with AD and 137 ethnically matched controls using ACE gene indel genotype association methods with logistic regression adjusted for other variables. Besides, 65 out of 257 AD patients, 11 with D/D genotype, 28 with I/I genotype and 26 with I/D genotype were recruited. Their plasma ACE protein levels were measured by enzyme-linked immuno-sorbent assay and compared for their corresponding ACE gene indel polymorphism.
patients with ACE-I/I homozygote were less likely to be associated with AD, compared with both I/D and D/D (OR: 0.601; 95% CI: 0.372-0.969; P = 0.037), or only I/D genotype (OR: 0.584; 95% CI: 0.349-0.976; P = 0.040). There were significantly different plasma ACE protein levels among these three different genotype groups (P = 0.023). The I/I genotype group had significantly lower ACE plasma levels [114.79 ± 31.32 ng/ml (mean ± SD)], compared with D/D (164.07 ± 86.36 ng/ml; P = 0.010), but not I/D (141.45 ± 51.50 ng/ml; P = 0.064).
ACE-I/I homozygote corresponds to lower plasma ACE protein level and it is independently but less likely to be associated with AD. These findings signal the importance of ACE indel polymorphisms to their corresponding protein levels and to AD.
... Controls 215 91/124 72.5 0.53/0.47 63 102 50 Margaglione et al (1996) 10 Cases 101 51/50 63.6 0.72/0.28 54 37 10 Positive 1.76 (1.02–3.05) ...
The angiotensin-1 converting enzyme (ACE) gene is known to have two polymorphic alleles I/D. People with the DD genotype have been shown to be at greater risk of myocardial infarction, but only in some studies. Similar studies in stroke patients also show inconsistent results, but most of these studies have been underpowered to detect a small contribution to stroke risk from the ACE gene. A meta-analysis was undertaken using all known publications of the ACE polymorphism in ischaemic stroke.
Two computerised databases were searched for all publications relating to case-control studies using the ACE I/D variant in human ischaemic stroke. Seven association studies were identified and a meta-analysis was conducted using the Mantel-Haenszel estimate for odds ratio (OR) to determine whether the DD genotype predicted outcome in either a genetically dominant or recessive model.
1918 white subjects (1196 cases and 722 controls) were used in the meta-analysis. There was no difference in ACE genotype (chi2=2.92, p>0.05) or I/D allele frequency (chi2=3.28, p>0.05) in cases or controls. The overall OR for the D allele as an independent risk factor in ischaemic stroke was 1.31 (95% confidence interval (95% CI): 1.06-1.62, p=0.01) under a recessive model, and 1.14 (95% CI: 0.91-1.44, p=0.26) under a dominant model.
This meta-analysis shows that the the D allele, acting recessively, is a modest but independent risk factor for ischaemic stroke onset. Meta-analysis may usefully be employed in allelic association studies for detecting small attributable risks of candidate genes in polygenic disorders.
... An early study showed a positive association between lacunar stroke and ACE polymorphism but no association with ICVD due to carotid stenosis [20]. Another study suggested that the DD genotype could discriminate subjects with a history of stroke [21]. However, other studies in different populations have failed to show associations [12,[22][23][24][25], except in hypertensive cerebrovascular disease [26]. ...
Ischaemic cerebrovascular disease (ICVD) is a heterogeneous syndrome to which different genetic factors may contribute. We have investigated the distribution of alleles of the angiotensin-converting enzyme (ACE) gene, which has been suggested to be of possible importance in ischaemic stroke or cardiovascular disease, in groups of patients with ischaemic stroke and carotid artery stenosis (CS).
One hundred and thirty patients with ischaemic stroke and 68 patients with more than 50% stenosis of the internal carotid artery were investigated and compared with age- and sex-matched healthy control subjects. Alleles of an insertion/deletion polymorphism of the ACE gene were determined by one-stage polymerase chain reaction and visualized on agarose gels.
There was a significant difference (P < 0.05) in the distribution of ACE alleles, homozygosity for the presumed susceptibility deletion allele being more common in patients with CS than in healthy control subjects. There was also a significant difference (P < 0.05) in patients with CS in comparison with matched ICVD patients without CS, both in allelic frequencies and in homozygosity for the deletion allele.
Our results indicate that the ACE gene polymorphism may be a risk factor for the development of CS. The observed difference in ACE allele distribution may be seen as evidence for a genetic distinction between ICVD and CS, two clinically related conditions, which further supports the hypothesis that genetic factors are of importance for this group of diseases.
... Coaggregation of hypertension and stroke in these relatives also suggests that genes influencing susceptibility to hypertension may also be risk factors for stroke. One such candidate is the angiotensin 1-converting enzyme gene, in which an insertion-deletion polymorphism has been associated with hypertension 30,31 and stroke, 32,33 although the role of angiotensin 1-converting enzyme in hypertension is controversial. 34,35 Alternatively, a common genetic basis for stroke and hypertension might be affected through genes underlying the risk factors for these traits (eg, obesity, atherosclerosis, diabetes). ...
The genetic basis of stroke is poorly understood. We evaluated patterns of familial aggregation of hypertension and stroke to test the hypothesis that inherited susceptibility to these disorders may be determined by a common set of factors.
Genealogical and medical history information was obtained for a cohort of 354 hypertensive probands ascertained in a clinic-based setting, their 1427 first-degree relatives, and 239 of their spouses. Risks of stroke and hypertension in biological and nonbiological relatives were compared with the logistic model of the generalized estimating equations adjusted for age and sex.
The risk of hypertension was higher for the parents and siblings of the probands than for spouses (odds ratio [OR]=2.4; 95% CI, 1.8 to 3.4; OR=2.2; 95% CI, 1.6 to 3.0, respectively). When the spouses were used as a reference group, the risk of stroke for parents of the hypertensive probands was 7.3 times higher (OR=7.3; 95% CI, 3.6 to 14.8), while a nonsignificant but slightly increased risk for siblings (OR=1.6; 95% CI, 0.8 to 3.3) was observed. Controlling for hypertension, obesity, smoking, coronary heart disease, diabetes, and cholesterol resulted in decreased estimates of the risk of stroke for parents and siblings (OR(parents)=5.4; 95% CI, 2.6 to 11.2; OR(siblings)=1.2; 95% CI, 0.6 to 2.5). The risk of stroke was significantly higher for hypertensive parents and siblings than for nonhypertensive parents (OR=5.2; 95% CI, 2.8 to 9. 7) and siblings (OR=5.8; 95% CI, 2.1 to 15.9). A history of hypertension was not associated with an increased risk for stroke in spouses (OR=0.7; 95% CI, 0.2 to 3.1). The risk of stroke in hypertensive relatives of probands with stroke was higher than that of the normotensive relatives (OR=13.4). A less elevated risk ratio was observed in the relatives of probands who did not have a stroke (OR=4.0).
Our data showing a higher occurrence of hypertension and stroke in parents of hypertensive probands compared with spouses suggest that some of the genetic factors predisposing to these conditions may be the same. The slightly increased risk to siblings compared with spouses was not significant, suggesting that elucidation of these factors through family studies of stroke may be difficult because of secular trends toward improved treatment for hypertension. Although a history of hypertension increases the risk of stroke among parents and siblings, multivariate analyses revealed a familial component to stroke independent of hypertension.
... Genetic influences on the components of this system and their impact on the development of CAD are gradually being elucidated. The I/D polymorphism in the ACE gene has engendered numerous reports of possible allelic influences on intermediate and complex phenotypes, such as, serum levels of ACE [3,14]; conversion of angiotensin I to angiotensin II [15] and blood pressure [15]; on risk factors, such as, hypertension [16,17], left ventricular function [18], and insulin resistance [19] ; and on outcomes , such as, MI [10,11], ischemic stroke [20] , hypertrophic cardiomyopathy [21], diabetes [19,22], and nephropathy [23]. Various approaches have been used to study the ACE I/D polymorphism in relation to coronary disease, blood pressure and diabetes. ...
An association between a polymorphism of the angiotensin-converting enzyme (ACE) gene and myocardial infarction (MI) in men has been previously reported. The present study examines the association between ACE genotype, atherosclerosis, MI, hypertension and other cardiovascular risk factors in Caucasian men (n=576) and women (n=124) who have undergone coronary angiography. Gene frequencies are also reported for African-American men (n=56). Genotype determination was based on the presence (allele I) or absence (allele D) of a 287 nucleotide Alu sequence in intron 16 of the ACE gene. Genotype frequencies for DD, ID and II were: 30.9, 47.7, 21.4% for Caucasian men; 28.2, 48.4, 23.4% for Caucasian women; and 30.4, 46.4, 23.2% for African-American men. There were no statistically significant associations between ACE genotype and number of plaques (> or =10% obstruction), lipid variables, or body mass index (BMI) for Caucasian men. Caucasian women with the DD genotype had on average fewer plaques, but this was accounted for by their younger ages. In Caucasian males, the DD genotype independently contributed to the presence of hypertension (odds ratio=1.8, 95% CI 1.1-2.9) after adjusting for age and BMI. In Caucasian males with total cholesterol levels less than 200 mg/dl (n=237), the DD (odds ratio=2.5, 95% CI 1.2-5.4) and ID genotypes (odds ratio=2.2, 95% CI 1.1-4.4) were associated with a history of MI.
... The main gene studied is angiotensinconverting enzyme (ACE) gene, specifically an insertion/deletion (I/D) polymorphism present in intron 16 of the gene. This variant, first identified by its association with myocardial infarction (Cambien et al., 1992), has been found to be positively associated with stroke in a number of independent studies Nakata et al., 1997;Margaglione et al., 1996;Doi et al., 1997;Kario et al., 1996;Watanabe et al., 1997;Castellano et al., 1995;Hosoi et al., 1996). A metaanalysis of the ACE gene in ischemic stroke also found a significant association between the occurrence of the homozygous deletion (D/D) polymorphism and stroke (Sharma, 1998). ...
As one of the leading causes of death within both the developed and developing world, stroke is a worldwide problem. Risk factors can be identified and controlled at the level of lifestyle changes; however, genetic components of stroke have yet to be identified. The identification of such genetic components is critical in the understanding, diagnosis, and treatment of stroke in the future. This review focuses on the genetic determinants of stroke in both human and experimental systems. Mendelian disorders, candidate genes, and twin studies provide evidence for a strong genetic component of stroke. Genome-wide scanning in both human and animal models has led to the identification of regions of the genome that contain genes for stroke susceptibility and sensitivity. Animal models of stroke allow for environmental control and genetic homogeneity, not possible within a human population, and therefore are essential for the dissection of this complex, multifactorial disorder. Future genetic and genomic strategies and their role in ultimate causative gene identification are discussed.
The possible association of ACE polymorphism with ischemic stroke (IS) was evaluated in 65 patients with IS and 330 age and BMI-matched controls. ACE genotypes were determined by polymerase chain reaction (PCR). There was no significant difference in ACE genotype/allele frequencies between case and control group (p>0.05). Patients with D allele had 4,7 times higher risk for large vessel IS than healthy persons D allele possessors. Persons with D allele had 9.2 times higher risk for large vessel disease than small vessel disease. These data suggest a possible association of ACE gene polymorphism with pathogenesis of large vessel IS.
The insertion/deletion (I/D) polymorphism at the locus for the angiotensin I converting enzyme (ACE) has been the focus of considerable interest since the report by Cambien and his co-workers (Cambien et al., 1992) of association between the D allele and coronary heart disease (CHD), particularly in CHD patients without classical risk factors. In the following, this observation by Cambien’s group will be compared with observations in our group and with some of the studies in the literature.
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
Background:
The association between the angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism and risk of ischemic stroke (IS) remains controversial and ambiguous. To clarify this association, a large meta-analysis was performed.
Methods:
Electronic databases in both English and Chinese were used to identify relevant studies (updated in February 2014). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to describe the strength of the association.
Results:
One hundred and fifty eligible studies, including 18,258 IS cases and 28,768 controls, were identified. Meta-analysis of these studies pointed to a significant association between the ACE I/D polymorphism and IS risk: (D vs. I: OR=1.354, 95% CI=1.272-1.440, P<0.001; DD vs. II: OR=1.755, 95% CI=1.561-1.973, P<0.001; ID vs. II: OR=1.178, 95% CI=1.098-1.263, P<0.001; DD vs.
Id/ii:
OR=1.535, 95% CI=1.399-1.684, P<0.001; DD/ID vs. II: OR=1.353, 95% CI=1.251-1.463, P<0.001). Subgroup analysis revealed a significantly elevated risk among Asians, but with borderline statistical significance among Caucasians.
Conclusion:
This meta-analysis indicated that the ACE I/D polymorphism may be a genetic susceptibility factor for IS, especially among Asians, but with borderline statistical significance for Caucasians. Further investigations are needed to validate our conclusions.
Genetic factors are involved in the development of diabetic nephropathy in type-1 diabetes. We are examining the association of the angiotensin-converting enzyme (ACE), insertion/deletion (I/D) polymorphism with the presence of diabetic nephropathy in type-1 diabetic patients. 52 type-1 diabetic patients with diabetic nephropathy (30 with either microalbuminuria or macroalbuminuria and 22 with end stage renal disease on dialysis) were compared with 10 type-1 diabetic patients with normoalbuminuria and duration of disease longer than 15 years and 27 non-diabetic healthy subjects. We found that the D-allele frequency was higher in patients with nephropathy than in the healthy and normoalbuminuric controls. There was an association in the DD polymorphism of the ACE gene with patients with diabetic nephropathy and not with the control subjects. We conclude that the DD genotype of ACE gene polymorphism is associated with diabetic nephropathy in patients with type-1 diabetes mellitus.
Many studies have investigated the association between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and risk of ischemic stroke. However, the evidence is inadequate to draw robust conclusions because most studies were generally small and conducted in heterogeneous populations. To shed light on these inconclusive findings, we conducted a large meta-analysis of studies relating the ACE I/D polymorphism to the risk of ischemic stroke.
Relevant studies were identified by searching PubMed and Embase through February 2012 and by reviewing the references of retrieved articles. We included studies that reported odds ratio (OR) with 95% confidence interval (CI) for the association between this polymorphism and ischemic stroke risk.
Fifty independent publications, with 10 070 stroke cases and 22 103 controls, were included. The results indicated that the DD homozygote carriers had a 37% higher risk of ischemic stroke when compared with the homozygotes II and heterozygote ID [odds ratio (OR) = 1.37, 95% confidence interval (CI): 1.22-1.53]. Subgroup analyses indicated that this higher risk was more pronounced among Asians, hospital-based studies, and small vessel disease (SVD). Potential publication bias may exist, but correction for this bias using a formal statistical method did not materially alter the combined risk estimate.
The results of our meta-analysis indicate that the D allele of ACE I/D polymorphism is a low-penetrance susceptibility marker of ischemic stroke.
The effector peptide of the renin-angiotensin system (RAS), angiotensin II (Ang II), can be directly generated in the brain independently of the peripheral RAS. Activation of angiotensin receptors in the brain induces the expression of inducible transcription factors involved in gene regulation. A number of animal studies and clinical trials have shown that the RAS is associated with the development of cardiovascular diseases and pathophysiological processes occurring in ischaemic stroke. Angiotensin-converting enzyme (ACE) inhibitors and selective AT1 receptor antagonists protect hypertensive subjects against stroke by reduction of blood pressure and improve the recovery from ischaemic insult by normalisation of cerebral blood autoregulation and improvement of collateral blood flow to the ischaemic tissue . In animal models, inhibition of the brain RAS proved to be beneficial with respect to stroke incidence and outcome. Blockade of cerebrovascular or brain AT1 receptors reduces the volume of ischaemic injury and improves the recovery from brain ischaemia. Remarkable progress has been made in elucidating the role of Ang II and its receptors in the control of pathophysiological events associated with stroke such as cerebral haemodynamics, apoptosis, inflammation, neuroregeneration and neuroprotection. In this chapter, we summarise the effects of Ang II in the brain on the expression of inducible transcription factors and possible target genes. The second part of the article reviews the effects of inhibition of ACE and angiotensin receptors in cerebral vessels and brain tissue on processes occurring during and after ischaemic injury and discusses the effects of AT1 receptor blockade on cerebral haemodynamics, neuroprotection and neuroregeneration. This chapter may also provide a framework for the development of new therapeutic strategies in the prevention and treatment of ischaemic stroke
It has been suggested that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is an independent risk factor for coronary artery disease, but its relation to cerebral infarction is still controversial. Plasminogen activator inhibitor 1 (PAI-1) is also a predictor of risk of atherothrombotic disease. In this study we investigated the association of the ACE gene polymorphism and plasma PAI-1 levels in subjects with cerebral infarction. We evaluated the genotype of the ACE gene in 26 subjects with and 28 subjects without a history of ischemic stroke. The ACE genotype was analyzed by the polymerase chain reaction. Plasma PAI-1 antigen levels were measured by ELISA. There were no differences in accepted risk factors between the groups with or without cerebral infarction. However, the frequency of the D allele was significantly higher in subjects with cerebral infarction (0.63) than in those without infarction (0.39) (2 = 6.306, P = 0.012). The frequency of the DD genotype of the ACE gene was also significantly higher in subjects with than in those without cerebral infarction (DD: 46.2%, ID: 34.6%, II: 19.2% vs. DD: 14.3%, ID: 50.0%, II: 35.7%, 2 = 6.689, P = 0.035). Plasma PAI-1 levels were not significantly different between groups with and without cerebral infarction. There was no association between the ACE genotype and PAI-1 levels. The DD genotype of the ACE gene is associated with cerebral infarction, which is independent of plasma PAI-1 level.
Acute ischaemic stroke has significant attendant morbidity and is one of the top ten causes of childhood death. It requires prompt investigation and management, however little is known about the safety and efficacy of acute thrombolytic therapies in childhood arterial ischaemic stroke. The authors report a case of a 13-year-old girl with an acute basilar thrombosis, successfully treated with intravenous recombinant tissue plasminogen activator and discuss the management of paediatric arterial ischaemic stroke.
Evidence from twin and family shows that genetic factors contribute to the risk of stroke and that their role may be at least as important in stroke as in coronary heart disease. Additional support for the significance of genetic factors comes from other findings such as epidemiological data showing phenotypic heterogeneity of stroke, genetic influence on many of the risk factors for stroke, and racial and geographic differences in morbidity and mortality in stroke victims. Yet, apart from the reported associations of a small number of cases with Mendelian cerebrovascular diseases, only a few studies have directly investigated gene markers or molecular genetics of stroke. This review presents the existing evidence on the genetic background of stroke and discusses results from the genetic studies of stroke published to date.
Matarin M, Singleton A, Hardy J, Meschia J (Laboratory of Neurogenetics, Bethesda, MD, USA; UCL Institute of Neurology, London, UK; Mayo Clinic, Jacksonville, FL, USA). The genetics of ischaemic stroke (Review). J Intern Med 2010; 267: 139–155.
In this review, we discuss the genetic factors in both the aetiology and treatment of ischaemic stroke. We discuss candidate gene association studies, family linkage studies and the more recent whole genome association studies and whole genome expression studies. We also briefly discuss genetic testing for stroke risk and genetic analysis of treatment complications.
Epidemiological studies suggests that migraine is associated with disorders of the cerebral, coronary, retinal, dermal and peripheral vasculature. There is evidence that migraine is associated with endothelial dysfunction, both as a cause and a consequence. Endothelial dysfunction, a vascular risk factor, is characterized by endothelial activation and impaired vascular reactivity. Plasma and genetic biomarkers for these conditions have been identified. The clinical significance lies in the potential for the rapid identification of migraineurs at increased risk of ischaemic stroke and vascular disease through ascertainment of endothelial dysfunction biomarkers. It is uncertain whether stroke, myocardial infarction and other vasculopathies can be prevented by migraine prophylaxis, endothelial repair, platelet inhibition or a combination of these strategies.
Stroke is a heterogeneous multifactorial disease. Hence, a large number of candidate genes are involved in stroke pathophysiology, such as blood pressure regulation and atherosclerosis. Although angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism is considered to have a role in hypertension, coronary artery disease, and myocardial infarction, its relationship with cerebrovascular disease and hypertension in stroke in different ethnic populations is still inconsistent.
ACE I/D polymorphism, detected by polymerase chain reaction (PCR), was studied in 97 patients with large-vessel and 60 patients with small-vessel atherosclerotic stroke (44 asymptomatic, 16 symptomatic lacunes) and 85 healthy subjects with normal brain imaging. The demographic data, lipid profile and risk factors of patients and controls were obtained retrospectively.
ACE genotypes were in Hardy-Weinberg equilibrium in both patients and controls. Prevalences of DD, ID and II genotype were 41%, 40%, and 19%, respectively, in the stroke group. Differences in ACE I/D polymorphism distribution were statistically insignificant between the groups. This lack of association between stroke and ACE I/D polymorphism did not change in the presence of traditional risk factors (hypertension, diabetes mellitus, smoking, and dyslipidemia). Although hypertension was significantly more common in the patient groups, ACE I/D polymorphism showed no effect on hypertension risk. This lack of association also did not change according to groups or in the presence of diabetes mellitus, male gender or smoking.
ACE I/D polymorphism did not predict the risk of stroke or hypertension in our population living in the western Black Sea region of Turkey.
Angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms are linked to endothelial dysfunction and to cerebral white matter lesions. Objectives of this study were to determine if ACE and MTHFR gene polymorphisms are associated with von Willebrand factor (vWF) activity, an endothelial dysfunction marker, and with a distinct headache phenotype. We enrolled 64 women (18-50 years old) with International Classification of Headache Disorders, 2nd edn migraine without aura (MoA) and 61 with aura (MA). Genotypic frequencies: ACE DD 35%, ID 42%, II 23%, and MTHFR TT 17%, CT 40%, CC 43%. Those with ACE DD genotype had higher levels of vWF activity (152%) compared with ID and II genotypes. Levels were highest (179%) with combined ACE DD and MTHFR TT genotypes. ACE DD was associated with higher headache frequency, and MTHFR TT was associated with MA. In migraine, vWF activity may be a marker of endothelial-mediated genetic risk for ischaemic conditions.
Despite recent advances in acute stroke therapy, stroke remains the leading cause of severe disability and the third leading cause of death, after heart disease and cancer, in Western countries and Japan. The identification of biomarkers of stroke risk is thus important both for risk prediction and for intervention to avert future events. Although genetic linkage analyses of families and sib-pairs as well as candidate gene and genome-wide association studies have implicated several loci and candidate genes in predisposition to ischemic or hemorrhagic stroke, the genes that contribute to genetic susceptibility to these conditions remain to be identified definitively. Given that vascular inflammation has been recognized as an important mechanism of atherosclerotic disease, proinflammatory genes may play pivotal roles in the pathogenesis of ischemic stroke. In this review, we summarize candidate genes that have been implicated in common forms of ischemic stroke by linkage analyses and association studies. We also review in more detail studies that have revealed an association of ischemic stroke with polymorphisms of proinflammatory genes of particular interest (LTA, IL6, and ALOX5AP) as well as with polymorphisms at chromosomal region 9p21.3, which has recently been identified as a susceptibility locus for coronary heart disease. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of ischemic stroke.
Available data on possible genetic impacts of mammalian retroposons are reviewed. Most important is the growing number of established examples showing the involvement of retroposons in modulation of expression of protein-coding genes transcribed by RNA polymerase II (Pol II). Retroposons contain conserved blocks of nucleotide sequence for binding of some important Pol II transcription factors as well as sequences involved in regulation of stability of mRNA. Moreover, these mobile genes provide short regions of sequence homology for illegitimate recombinations, leading to diverse genome rearrangements during evolution. Therefore, mammalian retroposons representing a significant fraction of noncoding DNA cannot be considered at present as junk DNA but as important genetic symbionts driving the evolution of regulatory networks controlling gene expression.
The D/I polymorphism of the ACE gene has been studied in relation to a variety of cardiovascular disorders, including stroke. A number of small studies have been conducted, with inconsistent results. We investigated the association between ACE genotype and the incidence of stroke in a large, prospective, matched case-control sample from the Physicians' Health Study.
In the Physicians' Health Study, 348 subjects who had been apparently healthy at enrollment suffered a stroke during 12 years of follow-up, as determined from medical records and autopsy. A total of 348 cases were matched by age, time of randomization, and smoking habit to an equal number of controls (who had remained free of stroke). The D/I polymorphism was determined by polymerase chain reaction. Data were analyzed for the entire nested case-control sample, and also among a subgroup without a history of hypertension or diabetes mellitus, considered to be at low conventional risk (207 cases and 280 controls). All observed genotype frequencies were in Hardy-Weinberg equilibrium. The relative risk associated with the D allele was 1.11 (95% CI, 0.90 to 1.37; P=0.35), assuming an additive model in the matched analysis. Additional analyses assuming dominant or recessive effects of the D allele, as well as the analysis after stratification for low-risk status, showed no material as a statistically significant association.
The results of this large, prospective study indicate that the ACE D/I gene polymorphism is not associated with subsequent risk of stroke.
Many authors have reported an association between the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. The study is aimed to evaluate if the DD genotype could also be associated with the frequency and duration of migraine without aura. In 302 patients suffering from migraine without aura (at least for 1 year), with no history of cardiovascular diseases and major risk factors for ischemic events, the genotypes of the ACE gene, plasma ACE activity, and the frequency (weekly) and duration of migraine attacks were evaluated. No drugs were given before (4 weeks) and during the study. The same evaluations were performed in 201 subjects without migraine. The molecular biologist and the physician evaluating the patient data were blinded to the clinical history and ACE-DD gene determination. Genotypes were determined by polymerase chain reaction amplification. Plasma ACE activity was performed by the HPLC method. The groups were similar for sex, age and smoking habit (migraines: 302 patients (200 F/102 M), mean age 37.8 ± 8.2 years; control: 201 subjects (127 F/74 M), mean age 37.5 ± 9.3 years). Patients with migraine without aura showed higher incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p Copyright
To determine the role of angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) polymorphisms in the pathogenesis of nonartertic anterior ischemic optic neuropathy (NAION).
Retrospective, case-control study.
Seventy-four patients with NAION diagnosed from 1984 through 1999. Seventy-one patients who visited the Eye Institute comprised the control group. TESTING INTERVENTION: DNA was extracted from whole blood obtained from all patients and control participants. Polymerase chain reaction (PCR) was used for analysis of ACE and AT1R polymorphisms.
The frequency of the polymorphism for ACE among the NAION patients (39.2% deletion allele [DD], 54.0% deletion/insertion [D/I] locus, 6.8% insertion allele [II]) was similar to that of the control group (50.7% DD, 39.4% D/I, 9.9% II), with P = 0.21. The frequency of the polymorphism of AT1R in the NAION patients was 5.4% CC, 44.6% CA, 50% AA, and in the control group it was 4.2% CC, 33.8% CA, 62.0% AA, with P = 0.35. Participants less than 55 years of age and those more than 55 had quite similar distributions.
Angiotensin converting enzyme and AT1R polymorphisms have no part in the mechanism of NAION. Thus drugs such as ACE inhibitors or AT1R antagonists are not specifically indicated for treatment of these patients.
Reduced glutathione (GSH) plays a critical role as an intracellular defense system providing detoxification of a broad spectrum of reactive species and their excretion as water-soluble conjugates. Conjugation of GSH with electrophiles is catalyzed by GSH S-transferases (GST), which constitute a broad family of phase II isoenzymes. Two of the GST encoding genes, GSTM1 (mu) and GSTT1 (theta), have a null genotype due to their homozygous deletion that results in lack of active protein. Polymorphisms within GSTT1 and especially GSTM1 have often been associated with cancer in various organs as well as with elevated levels of DNA adducts in various cell types. We recently demonstrated that DNA adducts are consistently detectable in smooth muscle cells (SMC) of human abdominal aorta affected by atherosclerotic lesions. Here we provide evidence that levels of adducts to SMC DNA from atherosclerotic lesions are consistently increased in individuals having the null GSTM1 genotype, whereas no association was established with the GSTT1 polymorphism. The influence of GSTM1 deletion was better expressed in never-smokers and ex-smokers than in current smokers. These findings bear relevance to the epidemiology of atherosclerosis and suggest that metabolic polymorphisms may contribute to the interindividual variability in susceptibility not only to carcinogens, but also to DNA binding atherogens.
Sequencing of the human genome is nearing completion and biologists, molecular biologists, and bioinformatics specialists have teamed up to develop global genomic technologies to help decipher the complex nature of pathophysiologic gene function. This review will focus on differential gene expression in ischemic stroke. It will discuss inheritance in the broader stroke population, how experimental models of spontaneous stroke might be applied to humans to identify chromosomal loci of increased risk and ischemic sensitivity, and also how the gene expression induced by stroke is related to the poststroke processes of brain injury, repair, and recovery. In addition, we discuss and summarise the literature of experimental stroke genomics and compare several approaches of differential gene expression analyzes. These include a comparison of representational difference analysis we have provided using an experimental stroke model that is representative of stroke evolution observed most often in man, and a summary of available data on stroke differential gene expression. Issues regarding validation of potential genes as stroke targets, the verification of message translation to protein products, the relevance of the expression of neuroprotective and neurodestructive genes and their specific timings, and the emerging problems of handling novel genes that may be discovered during differential gene expression analyses will also be addressed.
Family history and twins studies suggest an inherited component to ischemic stroke risk. Candidate gene association studies have been performed but have limited capacity to identify novel risk factor genes. The Siblings With Ischemic Stroke Study (SWISS) aims to conduct a genome-wide scan in sibling pairs concordant or discordant for ischemic stroke to identify novel genetic risk factors through linkage analysis.
Screening at multiple clinical centers identifies patients (probands) with radiographically confirmed ischemic stroke and a family history of at least 1 living full sibling with stroke. After giving informed consent, without violating privacy among other family members, the proband invites siblings concordant and discordant for stroke to participate. Siblings then contact the study coordinating center. The diagnosis of ischemic stroke in potentially concordant siblings is confirmed by systematic centralized review of medical records. The stroke-free status of potentially discordant siblings is confirmed by validated structured telephone interview. Blood samples for DNA analysis are taken from concordant sibling pairs and, if applicable, from 1 discordant sibling. Epstein-Barr virus-transformed lymphoblastoid cell lines are created, and a scan of the human genome is planned.
Conducting adequately powered genomics studies of stroke in humans is challenging because of the heterogeneity of the stroke phenotype and the difficulty of obtaining DNA samples from clinically well-characterized members of a cohort of stroke pedigrees. The multicentered design of this study is intended to efficiently assemble a cohort of ischemic stroke pedigrees without invoking community consent or using cold-calling of pedigree members.
We studied polymorphisms of mitochondrial DNA 5178cytosine/adenine (mt5178C/A) and angiotensin I-converting enzyme (ACE) genes (DCP1) in 127 cerebrovascular disorder (CVD) patients and 294 age-matched normal controls to clarify the genetic background of Japanese patients with CVD. Mt5178C was predominant in CVD patients compared with controls (P<0.01). The frequency of DCP1 insertion (I) and deletion (D) alleles showed no significant difference between the CVD patients and controls or between each CVD subgroup. Although the number of CVD patients in the present study was too small to make a final conclusion, mt5178C might be one of the genetic factors to be considered in Japanese patients with CVD.
Periodontal diseases belong to the most common chronic disorders affecting mankind. Smoking and impaired plasminogen activation with hypercoagulation and fibrinolysis inhibition have been proposed as having a role in predisposition to these diseases. We investigated relationships among adult periodontitis, smoking, and a variation in the deletion/insertion (4G/5G) promoter polymorphism of the plasminogen-activator-inhibitor-1 (PAI-1) gene in 304 Caucasian subjects. An association was detected between the deletion (4G) allele (and 4G/4G genotype) and periodontitis (P = 0.0022, P(corr) < 0.01; P = 0.014, P(corr) < 0.05). A stronger association occurred in non-smokers (P = 0.00021, P(corr) < 0.01; P = 0.0024, P(corr) < 0.05) where the presence of the PAI-1 gene 4G allele appears to be one of the risk factors for periodontitis.
To evaluate how angiotensin-converting enzyme (ACE) gene polymorphism is associated with perioperative blood loss in hip arthroplasty in a geriatric population.
A case-control study of subjects consecutively undergoing total hip arthroplasty.
A department of orthopedic surgery in Italy.
One hundred five patients, mean age +/- standard deviation 68.6 +/- 10.4, undergoing total hip arthroplasty.
ACE gene polymorphism was analyzed using polymerase chain reaction. Decrement of hemoglobin (Hb) and hematocrit (Ht) was calculated as the difference between the preoperative and the lowest postoperative value, measured 1, 2, and 3 days after surgery. Total blood loss was calculated as the sum of intra- and postoperative blood loss.
Patients carrying the deletion homozygous and insertion/deletion heterozygous genotypes of the ACE gene show a higher decrement of Hb (P <.01) and Ht (P <.01) and higher total blood loss (P <.007) after hip surgery than subjects carrying the insertion (II) homozygous. The role of ACE gene polymorphism seems hypertension independent. Logistic regression analysis showed that II genotype reduces total blood loss.
This is the largest study evaluating the distribution of ACE gene genotypes in patients undergoing hip arthroplasty and the first investigating the association between bleeding and ACE gene polymorphism. Our data suggest that II genotype is associated with lower total blood loss.
Evidence of inflammatory phenomena associated with atherosclerotic plaques is extensive. Interleukin-1 (IL-1) is one of the key modulators of the inflammatory response, and its activity is critically regulated by its receptor antagonist (IL-1Ra). A variable number of tandem repeats (VNTR) in intron 2 of the human IL-1Ra shows a common polymorphism that has been related to different production of IL-1Ra and IL-1 proteins. In monocytes, the less common allele 2 has been associated with an increased production of IL-1Ra and a decreased production of IL-1. Moreover, a cooperative effect with a C to T polymorphism in the promoter of IL-1β gene (C–511→T) has been described. In the present study, we investigated the frequency of these polymorphisms in 110 subjects who survived an ischemic stroke, in 101 healthy age-matched individuals, and in a population-based sample of 1,303 healthy Italians. The frequency of the IL- 1Ra 1/1 genotype was significantly higher in stroke survivors with respect to age-matched controls (77.2 and 45.5%, respectively; p –511→T) polymorphism. However, in stroke survivors, an association between the Ra*1 allele and the C allele of the IL-1β (-511) polymorphism was found (p
Nitric oxide is suggested to play a role in the development of preeclampsia.
We studied 61 patients with gestational hypertension (GH), 77 with GH and significant proteinuria (urine protein excretion > or = 300 mg/24 h), 82 with essential hypertension (EH) and 188 normotensive women with at least one normal pregnancy.
A polymorphism within the constitutive endothelial nitric oxide synthase (ecNOS) gene in various types of hypertension in pregnancy was explored.
Allelic and genotypic frequencies did not differ between controls and case groups. A significant difference was observed between the frequency of the rare allele in GH patients and that in EH group (chi2: 4.47, P <.04). This difference approximated the significance when GH subjects with or without proteinuria were grouped (chi2 square: 3.33; P =.068). Cigarette smoking or gravidity did not interact with the ecNOS polymorphism in identifying different types of hypertension in this setting.
Our findings argue against an association between ecNOS polymorphism and preeclampsia and support the hypothesis for a different pathogenesis of GH in respect to EH.