Association between angiotensin I-converting enzyme gene polymorphism and hypertension in selected individuals of the Bangladeshi population

The genetic factors that contribute to the development of coronary artery disease (CAD) are poorly understood. It is likely that multiple genes that act independently or synergistically contribute to the development of CAD and the outcome. Recently, an insertion/deletion (I/D) polymorphism of the human angiotensin I-converting enzyme (ACE) gene, a major component of the reninangiotensin system (RAS), was identified. The association of the ACE gene D allele with essential hypertension and CAD has been reported in the African-American, Chinese, and Japanese populations. However, other studies have failed to detect such an association. It has been suggested that these inconsistencies may be due to the difference in backgrounds of the population characteristics. In the present study, we investigated the I/D polymorphism of the ACE gene in 103 subjects of both sexes, consisting of 59 normal controls and 44 patients with hypertension. The allele and genotype frequency were significantly different between the hypertensive and control groups (p < 0.01). Among the three ACE I/D variants, the DD genotype was associated with the highest value of the mean systolic blood pressure [SBP] and mean diastolic blood pressure [DBP] (p = < 0.05) in men, but not in women. In the overall population, the mean SBP and DBP was highest in DD subjects, intermediate in I/D subjects, and the least in II subjects     

Deletion polymorphism of the angiotensin I-converting enzyme gene in elderly patients with coronary heart disease

Controversy exists as to whether the deletion/deletion (DD) genotype of angiotensin l-converting enzyme (ACE) gene polymorphism is associated with coronary heart disease (CHD). There are only a few studies dealing with this issue in the elderly, also with controversial results. The aim of this study was the assessment of correlation between genetic markers and the risk of CHD in the elderly. The results indicated DD genotype importance for CHD in the elderly as proven by discriminant analysis (chi2 = 25.77; df = 16; p = 0.0620). However, the use of univariate method demonstrated no correlation between DD genotype of ACE gene polymorphism and coronary artery disease. D allele of ACE gene was associated with higher activities of ACE plasma. A weak, but increased risk of MI is associated with high frequency of DD genotype in the elderly. Strong correlation between ACE polymorphism and ACE plasma activities was demonstrated.     

Association of angiotensin I-converting enzyme gene insertion/deletion polymorphism with rheumatic heart disease in Indian population and meta-analysis

Rheumatic heart disease (RHD) is one of the most severe consequences of rheumatic fever. It has been suggested that angiotensin I-converting enzyme (ACE) may be involved in the increased valvular fibrosis and calcification in the pathogenesis of RHD. We conducted a case–control study to look for association of ACE I/D polymorphism with RHD in Indian population. The study incorporated 300 patients (170 males and 130 females) with RHD, and 200 controls (118 males and 82 females). We also subgrouped RHD patients into mitral valve lesion (MVL) and combined valve lesion (CVL). ACE I/D polymorphism was identified using polymerase chain reaction method. We also performed a meta-analysis of three published studies and the present study (636 RHD cases and 533 controls) to evaluate the association between the ACE I/D polymorphisms and RHD risk. A significant difference in ACE ID and DD genotypes distribution between RHD cases (OR = 1.62, 95 % CI = 1.11–2.36 and OR = 2.08, 95 % CI = 1.02–4.15, respectively) and corresponding controls was observed. On comparing the ACE genotypes of MVL and CVL subgroups with controls, ID and DD genotypes were also significantly associated with CVL (FDR Pcorr = 0.009, OR = 2.19 and FDR Pcorr = 0.014, OR = 3.29, respectively). Meta-analysis also suggested association of the ACE D allele (FDR Pcorr = 0.036, OR—1.22, 95 % CI 1.02–1.45) with RHD. In conclusion, ACE ID and DD genotypes are associated with an increased risk of RHD, particularly CVL. This suggests that the ACE I/D gene polymorphism may play an important role in the pathogenesis of RHD.     

Human angiotensin I-converting enzyme gene and endurance performance.

Human physical performance is strongly influenced by genetic factors. A variation in the structure of the human angiotensin I-converting enzyme (ACE) gene has been reported in which the insertion (I) variant is associated with lower ACE levels than the deletion (D) gene. We have previously reported that the I variant was associated with improved endurance performance in high-altitude mountaineers and British Army recruits. We now examine this genotype distribution in 91 British Olympic-standard runners (79 Caucasians). DNA was extracted from the buccal cells contained in 10 ml of saline mouthwash donated by the subjects, and the I and D variants of the ACE gene were identified by PCR amplification of the polymorphic region. There was an increasing frequency of the I allele with distance run [0.35, 0.53, and 0.62 for /=5,000 m (n = 34), respectively; P = 0.009 for linear trend]. Among 404 Olympic-standard athletes from 19 other mixed sporting disciplines (in which endurance performance was not necessarily a key factor), the I allele did not differ significantly from that found in control subjects: 0.50 vs. 0.49 (P = 0.526). These results support a positive association of the I allele with elite endurance performance.     

Association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and essential hypertension in young Pakistani patients

Several studies have demonstrated the importance of angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphisms in the pathogenesis of hypertension. This study sought to determine the association between the ACE I/D polymorphism and essential hypertension in young Pakistanis. The frequency of the ACE I/D polymorphism was established by a comparative cross-sectional survey of Pakistani patients suffering from essential hypertension and ethnically matched normotensive controls. Samples were collected from tertiary care hospitals in northern Pakistan. Hypertensive individuals were defined as those with a systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg on three separate occasions, or those currently receiving one, or more, anti-hypertensive agents. DNA samples obtained from hypertensive (n = 211) and normotensive (n = 108) individuals were typed by PCR. The frequency of the ACE I/I genotype was significantly higher in hypertensive patients, aged 20-40 years, than in normotensive controls of the same age group (chi(2) = 4.0, P = 0.041). Whereas no overall significant differences were observed between the I/I, I/D and D/D ACE genotypes (One way ANOVA, F = 0.672; P = 0.413). The association between the ACE I/I genotype and essential hypertension in individuals aged 相似文献   

Functional study of the germinal angiotensin I-converting enzyme promoter.

Polymerase chain amplification experiments indicate that the germinal specific promoter of the angiotensin I-converting enzyme (ACE) is completely extinguished in somatic tissues. Despite this very strict specificity of expression, the germinal ACE promoter is active in transient transfection experiments in two somatic cell lines and one cell line of germinal origin. The analysis of the promoter shows the existence two regulatory elements within the first 350 bp: a proximal positive element and a distal negative element.     

Purification of angiotensin I-converting enzyme from human lung.

Angiotensin I-converting enzyme (peptidyl dipeptide hydrolase, EC 3.4.15.1) was solubilized from the membrane fraction of human lung using trypsin treatment and purfied using columns of DE 52-cellulose, hydroxyapatite and Sephadex G-200. The purified enzyme was shown to convert angiotensin I to angiotensin II and also to inactivate bradykinin. The specific activity of the enzyme was 9.5 units/mg protein for Hippuryl-His-Leu-OH and 0.665 mumol/min per mg protein for angiotensin I. The enzymic activity obtained after trypsin treatment (1 mg/200 mg protein) for 2 h could be divided into three components: (i) an enzyme of molecular weight 290 000 (peak I), (ii) an enzyme of molecular weight 180 000 (peak II) and (iii) an enzyme of molecular weight 98 000 (peak III), by columns of DE 52-cellulose and Sephadex G-200. Km values of peak I, II and III fraction for Hippuryl-His-Leu-OH were identical at 1.1 mM. pH optimum of the enzyme was 8.3 for Hippuryl-His-Leu-OH.     

An angiotensin I-converting enzyme insertion/deletion polymorphism is associated with Pakistani asthmatic cases and controls

Asthma is a chronic disease due to inflammation of the airways of lungs that is clinically characterized by variable symptoms including wheezing, coughing and shortness of breath. Angiotensin I-converting enzyme (ACE) plays a major role in fibrous tissue formation and is highly expressed in lungs. The main aim of this research work was to study the role of ACE insertion/deletion (I/D) polymorphism, rs4646994, in asthma in Pakistani patients. A total of 854 subjects, including 333 asthma patients and 521 ethnically matched controls, were studied. The ACE (I/D) polymorphism was genotyped using polymerase chain reaction (PCR). Chi-square, Fisher’s exact and Hardy–Weinberg equilibrium tests were used to compare groups. Homozygous insertion genotype II (p<0.0001, OR=3.38) and insertion allele (I) was significantly more frequent in Pakistani asthmatics than in healthy controls (p=0.0007, OR=1.40). The ID genotype (p<0.0001, OR=0.43) and the deletion allele (D) were associated with protection of disease in Pakistani patients (p=0.0007, OR=0.71). These data suggest the involvement of ACE I/D polymorphism in asthma risk in the Pakistani population. This marker may be an important indication in the molecular mechanism of asthma and can become a useful tool in risk assessment and help in designing strategy to combat disease.     

Association of T174M polymorphism of angiotensinogen gene with essential hypertension: A meta-analysis

The association between T174M polymorphism of angiotensinogen gene and essential hypertension risk remains controversial. We herein performed a meta-analysis to achieve a reliable estimation of their relationship. All the studies published up to May 2013 on the association between T174M polymorphism and essential hypertension risk were identified by searching the electronic repositories PubMed, MEDLINE and EMBASE, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Ultimately, nine eligible studies, including 2188 essential hypertension cases and 2459 controls, were enrolled in this meta-analysis. No significant associations were found under the overall ORs for M-allele comparison (M vs. T, pooled OR 0.92, 95% CI 0.62–1.37), MM vs. TT (pooled OR 0.86, 95% CI 0.29–2.51), TM vs. TT n (pooled OR 0.91, 95% CI 0.63–1.32), recessive model (MM vs. TT+TM, pooled OR 0.89, 95% CI 0.35–2.30), dominant model (MM+TM vs. TT, pooled OR 0.91, 95% CI 0.60–1.38) between T174M polymorphism and risk for essential hypertension. This meta-analysis suggested that the T174M polymorphism of the angiotensinogen gene might not be associated with the susceptibility of essential hypertension in Asian or European populations.     

睡眠中间歇低氧伴高血压患者与不同血管紧张素转换酶基因型关系的研究

目的探讨睡眠中间歇低氧-阻塞性睡眠呼吸暂停低通气综合征(OSAHS)伴高血压患者与血管紧张素转换酶(ACE)基因插入/缺失(I/D)多态性的关系。方法采用聚合酶链反应技术对2009年1月至2009年12月沈阳医学院奉天医院经多导睡眠监测(PSG)诊断为OSAHS且伴高血压的51例患者(试验组)及60例健康人进行ACE基因型检测,分析ACE基因型(ID组、II组及DD组)与OSAHS伴高血压患者之间关系。结果与对照组相比,试验组DD基因型显著高于II和ID基因型,等位基因频率D显著高于I(P<0.01),收缩压、舒张压、呼吸暂停低通气指数(AHI)水平显著高于对照组(P<0.01),夜间平均血氧饱和度(平均SaO2)显著低于对照组(P<0.01)。试验组中DD基因型频率显著升高(P<0.01),与ID、II基因型对比,收缩压及AHI均显著升高(P<0.05,P<0.01),平均SaO2显著低于对照组(P<0.05),男患多见(P<0.01)。随AHI增加,D等位基因表达增高,收缩压显著升高,平均SaO2显著降低。结论OSAHS伴高血压患者与ACE基因DD基因型相关,D等位基因可能为易感基因。OSAHS是高血压的独立危险因素,OSAHS越重,血压越高,且男性多发。     

Interaction of angiotensin I-converting enzyme with two potent tricyclic inhibitors

Inhibition of rabbit lung angiotensin I-converting enzyme was studied with two inhibitors that combined tricyclic mimics of a substrate C-terminal dipeptide recognition unit with a 4-phenylbutanoic acid fragment. The overall inhibition constant for [4S-[4 alpha, 7 alpha(R*),12b beta]]-7-[S-(1-carboxy-3-phenylpropyl) amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a] [2] benzazepine-4-carboxylic acid (MDL 27,088) was approximately 4 pM, whereas that for [4R-[4 alpha, 7 alpha(S*), 12b beta]]-7-[S-(1-carboxy-3-phenylpropyl)amino]-3,4,6,7,8, 12b-hexahydro-6-oxo-1H-[1,4]thiazino[3,4-a] [2]benzazepine-4-carboxylic acid (MDL 27,788) was estimated to be 46 pM. The formation of an initial complex of target enzyme and MDL 27,088 and its slower isomerization to a second complex were characterized kinetically. Both compounds appear to be among the most potent inhibitors known for this enzyme.     

Physicochemical characteristics of homogeneous bovine lung angiotensin I-converting enzyme. Comparison with human serum enzyme

Angiotensin I-converting enzyme was purified to electrophoretic homogeneity (12 units/mg) from bovine lung tissue and from human serum using an affinity gel described previously (Harris et al., (1981) Anal. Biochem. 111, 227-234). The isoelectric point (4.5), molecular weight (145 000), S20,W (8.1), amino acid composition and carbohydrate content of the lung enzyme are all similar to the values obtained for the human serum enzyme. The NH2-terminus of the lung enzyme (Ala) is different from that of the serum enzyme (Tyr) but the COOH-terminal sequences are identical (-Leu-Ser-OH). Pure bovine lung enzyme was reduced and carboxyamidomethylated with iodo (14C1) acetamide to the extent predicted by the number of cysteine residues. Since no radioactivity was incorporated into denatured enzyme that was not reduced, all of the cysteine residues must be in the form of disulfide bonds. Reverse-phase HPLC was used to separate peptides obtained from the lung enzyme after degradation with either trypsin or cyanogen bromide. The number of peptides resolved (42 after trypsin, 31 after cyanogen bromide), were only 20% fewer than the number predicted from the amino acid analysis and therefore the possibility that the converting enzyme (a single polypeptide chain) might be a fused dimer is excluded.     

Testicular angiotensin I-converting enzyme (E.C. 3.4.15.1)

In the two mammalian species (i.e., rabbit and rat) in which it has been studied to date, testicular angiotensin I-converting enzyme possesses distinct physicochemical and immunological properties, and a susceptibility to hormonal regulation that makes it a unique isozyme of the converting enzyme ordinarily distributed throughout the body. The testicular isozyme appears to be a lower molecular weight version of the pulmonary enzyme, with similar, although not identical, catalytic properties. The testicular isozyme is under androgenic control and is associated with germinal cells. Although its function has yet to be elaborated, the testicular isozyme provides an excellent model for the study of tissue-specific regulation of carboxypeptidases.     

Sequencing of an active-site peptide of angiotensin I-converting enzyme containing an essential glutamic acid residue

A glutamic acid residue at the active site of bovine lung angiotensin I-converting enzyme, a zinc-metallo peptidyl dipeptidase, was esterified with p-[N,N-bis(chloroethyl)amino]phenylbutyryl-L-[U-14C]proline (chlorambucyl-L-[U-14C]-L-proline), an affinity label for this enzyme (Harris, R.B., and Wilson, I.B. (1983) J. Biol. Chem. 258, 1357-1362). The radiolabeled enzyme was digested with BrCN and only 1 of the 30 cleavage peptides resolved by reverse-phase high performance liquid chromatography (HPLC) contained the bound radiolabel. This active-site peptide (Mr = 16,000) was digested with trypsin and the labeled peptide formed (T-2) was further degraded with thermolysin. The thermolytic peptides were resolved by reverse-phase HPLC. Only 1 of the 5 peptides obtained (Th-1, Mr = 1290) contained the bound radiolabel. Th-1 (12 residues) was subjected to manual Edman degradation and the following partial sequence was determined: H2N-Phe-Thr-Glu-Leu-Ala-Asp-Ser-Glu... The radiolabel was released at cycle 3 and the amount recovered was equivalent to the amount of phenylthiohydantoin-Glu detected on HPLC. Thus, glutamic acid is esterified with chlorambucyl-L-[U-14C]proline in confirmation of our earlier findings. The sequence determined is homologous in 5 residues with the corresponding sequences of bovine carboxypeptidase A and B, two other mammalian zinc proteases. There is little sequence homology with thermolysin, a bacterial zinc protease that also contains an essential active-site glutamic acid residue.     

Dipeptide-hydroxamates are good inhibitors of the angiotensin I-converting enzyme

The inhibition constants (Ki) and modes of inhibition have been determined for a series of dipeptide-hydroxamate compounds with bovine lung parenchyma angiotensin I-converting enzyme (peptidyldipeptide carboxy-hydrolase, E.C. 3.4. 15.1). The hydroxamido function was borne by aspartic, glutamic, or aminoadipic acid and extended by 2, 3 or 4 bond lengths from the proline amide bond. L-glu(NHOH)-L-pro (Ki = 3.4 microM) and D,L-aminoadipicyl (NHOH)-L-pro (Ki = 1.2 microM) were the best competitive inhibitors of the hydrolysis of benzoyl-gly-his-gly but were not effective as affinity ligands for purification of the enzyme.