Association of a polymorphism of the angiotensin I-converting enzyme gene with essential hypertension.

Angiotensin I-converting enzyme (ACE) is responsible for production of angiotensin II and breakdown of kinins, leading to increased blood pressure (BP). Furthermore, ACE inhibitors are effective antihypertensive agents. A 287 bp insertion/deletion polymorphism in intron 16 of the ACE gene (ACE) was examined by PCR in a cross-sectional study of 80 hypertensive (HT) and 93 normotensive (NT) subjects whose parents had a similar BP status at age greater than or equal to 50. The frequency of the insertion allele was 0.56 in HTs and 0.41 in NTs, and the difference between observed alleles in all subjects in each group was significant (chi 2 = 7.6, P less than 0.01). The data thus provide evidence in favour of an association of HT with a polymorphism at the ACE locus (17q23), so implicating this locus, and possibly a genetic variant of ACE itself, in human essential hypertension.     

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.     

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 converting enzyme gene I/D polymorphism of vitiligo in Korean population

Vitiligo (leukoderma) is an acquired idiopathic hypomelanotic disorder characterized by the circumscribed depigmented patches. Vitiligo is a polygenic disease. The exact pathogenesis is not yet known. The angiotensin converting enzyme (ACE) gene was selected as a candidate gene as ACE plays an important role in the physiology of the vasculature, blood pressure and inflammation, and its relationship with various diseases, including autoimmune diseases, has been widely investigated. The I/D polymorphism of ACE gene in vitiligo patients has not been reported. In this study, we investigated ACE gene polymorphism in 120 vitiligo patients and in 429 healthy volunteers in Korea. The ACE gene genotype distribution (P = 0.032) and allele frequency (P = 0.012) were significantly different between vitiligo patients and healthy controls. This study suggests that the ACE gene polymorphism has a strong association with the development of vitiligo in Korean patients.     

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.     

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。     

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   

Association study of CRP gene polymorphism and hypertension in Han Chinese population

Background

Serum C-reactive protein (CRP) and genetic variation of CRP gene have been reported as a strong, independent predictor of myocardial infarction and stroke. But there is rare association evidence of CRP genetic variation and hypertension (HT).

Methods

A community-based case–control study including 1331 cases with HT and 1400 controls was used to evaluate the association of tagSNPs covered CRP gene, CRPP1 gene and 40 kb upstream with HT in a Chinese Han population. Haplotypes and stratification analysis were applied to further evaluate relationships between the screened SNPs and HT and general linear model (GLM) was applied to compare blood pressure levels between genotypes.

Results

In stage 1, five SNPs had positive association with HT (P < 0.05) and entered stage 2 and two SNPs rs876537 and rs10737175 polymorphisms showed significant association with HT in joint sample. Haplotype analysis showed that comparing with common haplotype T–C which was constructed by rs6677719 and rs10737175, haplotype T–T significantly associated with HT after adjusted covariates. Stratification analysis found significant associations of HT for rs876537, rs2808630, rs6677719 and rs10737175 in ≥ 50 years group, rs876537, rs10737175 in female, rs876537 and rs10737175 in non-smoking and non-drinking populations as well as rs2808630 in non-drinking population. Furthermore, quantitative trait analysis indicated significant differences of SBP and DBP between the genotypes of rs10737175, rs876537 and rs2808630 in non-treatment hypertensive cases and control population.

Conclusions

The findings of this study support that CRP gene polymorphisms have significant association with genetic susceptibility of HT and quantitative traits of blood pressure.     

Association study of AGER gene polymorphism and hypertension in Han Chinese population

Background

Advanced glycation end products (AGEs) are produced by non-enzymatic glycation or glycoxidation of proteins, lipids and nucleic acids. The bond of AGEs and the receptor of AGE (AGER) in a pro-oxidant environment could induce immune and inflammation reaction involved in progress of microvascular disease. Accumulated evidence warrant further study on AGE–AGER pathway and genetic susceptibility to hypertension (HT).

Methods

We designed a two-stage association study to evaluate the association of AGER polymorphism and HT. In stage 1, seven tagSNPs were tested in 524 cases and 531 controls and the significant SNPs (P < 0.05) would enter into stage 2 including 807 cases and 869 controls. Furthermore, joint analysis was performed for all 2731 subjects including 1331 cases and 1400 controls, and meta-analysis was applied to evaluate combined estimations from the subgroups of stage 1 and stage 2.

Results

In stage 1, rs204994 had significant association with HT (P < 0.05) and enter stage 2. Neither joint analysis nor meta-analysis found statistical association of rs204994 with HT after adjusted for the covariates in the whole population. However, further stratification analysis found that rs204994 was significantly associated with HT in < 50 years and ≥ 50 years groups, ORs (95%CI) of dominant model were 1.623 (1.054–2.500) and 0.721 (0.546–0.952) respectively. No significant correlation was found between blood pressure and the polymorphisms of rs204994.

Conclusions

Our data suggests that age might modulate the genetic effects of variation of rs204994 in AGER on HT and further replications in other populations and functional studies should be warranted.     

Association between angiotensin-converting enzyme gene polymorphism and coronary artery disease

An insertion/deletion (I/D) polymorphism in the gene for angiotensin-converting enzyme (ACE) is associated with myocardial infarction and other cardiac pathology. There is evidence for a role of the renin-angiotensin system in cell growth and in the repair of damaged arterial walls, so the ACE gene is postulated to be a candidate gene affecting the important clinical problem of coronary artery disease (CAD). In view of the clinical importance of the ACE as a major marker of cardiovascular diseases, we investigated the I/D polymorphism of the ACE gene in Turkish CAD patients in comparison with control subjects to evaluate a possible association between CAD and the gene encoding ACE. Polymerase chain reaction, restriction fragment length polymorphism, and agarose gel electrophoresis techniques were used to determine the ACE genotype in 58 subjects. The frequencies of ACE D and ACE I allele among the patients with CAD were 62.26% and 37.73 % and in the control subjects were 49.3% and 50.76%, respectively. The greater frequency of deletion allele (D) was in the CAD group than in the control subjects was significant (P < 0.01).     

Association study between the angiotensin converting enzyme gene insertion/deletion polymorphism and Qinghai Han Chinese with congenital heart disease

Objective: The aim of this work is to determine whether the angiotensin converting enzyme(ACE) I/D(insertion/deletion) polymorphism is associated with the susceptibility to congenital heart disease(CHD) in the Qinghai Han Chinese. Methods: This study enrolled 59 CHD patients and 193 CHD controls from Qinghai Cardiovascular Diseases Vocational Hospital. Blood samples were collected from each of the patient and control groups. The ACE-I/D polymorphism was detected by polymerase chain reaction(PCR). Results: The genotype frequencies of ACE-I/D for II, ID, DD in patients and controls were 0.475, 0.441, 0.085 and 0.430, 0.446, 0.124, respectively. The allelic frequencies of I and D were 0.650, 0.350 and 0.695, 0.305, respectively. The OR of ID, DD and D alleles relative to II for CHD was 1.116(0.604-2.060), 1.619(0.564-4.648) and 1.211(0.777-1.889). There was no significant difference of the genotypic and the allelic frequencies in ACE-I/D polymorphism between the patient and control groups. Conclusion: There is no relation between ACE-I/D polymorphism and CHD in current Qinghai Han Chinese.     

Polymorphism of the promotor region of the angiotensinogen gene and the gene for angiotensin I-converting enzyme in arterial hypertension and myocardial ischemia of the Kazakh ethnic groups

Polymorphism of the promoter region of the angiotensinogen gene (ATG) and an angiotensin I-converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism were studied in three different groups of Kazakhs (control group, patients with cardiovascular disease (CAD) and patients with arterial hypertension (AH)) using three methods. A comparative analysis of the distribution of genotype and allele frequencies was conducted.     

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.     

Defining the boundaries of the testis angiotensin I-converting enzyme ectodomain

Numerous cytokines, receptors, and ectoenzymes, including angiotensin I-converting enzyme (ACE), are shed from the cell surface by limited proteolysis at the juxtamembrane stalk region. The membrane-proximal C domain of ACE has been implicated in sheddase-substrate recognition. We mapped the functional boundaries of the testis ACE ectodomain (identical to the C domain of somatic ACE) by progressive deletions from the N- and C-termini and analysing the effects on catalytic activity, stability, and shedding in transfected cells. We found that deletions extending beyond Leu37 at the N-terminus and Trp616 at the C-terminus abolished catalytic activity and shedding, either by disturbing the ectodomain conformation or by inhibiting maturation and surface expression. Based on these data and on sequence alignments, we propose that the boundaries of the ACE ectodomain are Asp40 at the N-terminus and Gly615 at the C-terminus.     

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 Klotho gene polymorphism with hypertension and coronary artery disease in an Iranian population

Background

Klotho, possibly an age-regulating protein, is considered an important factor contributing to the lifespan and pathophysiology of hypertension and coronary artery disease (CAD). The present study was carried out aiming to investigate the association of Klotho-rs564481 (C1818T) gene polymorphism with hypertension and CAD.

Methods

A total of 286 CAD-suspicious subjects were entered into this case-control study. The polymorphism was investigated in hypertensive patients with no CAD (H-Tens, n?=?60); hypertensive patients with CAD (CAD?+?H-Tens, n?=?95); CAD patients with no hypertension (CAD, n?=?61); and non-hypertensive non-CAD subjects, which were regarded as the control group (Ctrl, n?=?70). Genotype and allele frequencies were assessed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

A significant difference was found in allele frequency of Klotho C1818T among the four research groups (P?=?0.03). It was also found that wild-type homozygote subjects were negatively associated with hypertension as compared to heterozygote ones (OR?=?0.07 [95% CI: 0.008–0.69] P?=?0.02). Moreover, in the subgroups older than 57?years old, dominant genetic model demonstrated a negative association with CAD combined with hypertension (OR?=?0.31 [95% CI: 0.10–0.95] P?=?0.04).

Conclusions

In conclusion, Klotho C1818T variant may be associated with a decreased risk of hypertension. Moreover, aging enhanced positive effects of the Klotho polymorphism on CAD combined with hypertension, indicating the possibility that the KLOTHO gene might play a part in the age-related occurrence of CAD combined with hypertension.

     

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.