Association of angiotensin-converting enzyme DD genotype with 24-h blood pressure abnormalities in normoalbuminuric children and adolescents with Type 1 diabetes.

AIMS: To assess the distribution of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in children and adolescents with Type 1 diabetes and to evaluate the association between ACE genotype and blood pressure (BP). METHODS: ACE genotypes were assessed in 124 normoalbuminuric, clinically normotensive Type 1 diabetic children and adolescents and 120 non-diabetic controls using polymerase chain reaction. Twenty-four-hour ambulatory BP monitoring was undertaken in all patients. RESULTS: ACE genotypes distributed in patients as follows: 34 (27%) DD, 57 (46%) ID, 33 (27%) II. The distribution was similar in the control group: DD in 28% (33), ID in 45% (54), and II in 27% (33). Patients with DD genotype had higher mean 24-h diastolic BP (73.8 +/- 6.2 vs. 70.2 +/- 5.0 and 69.7 +/- 6.3 mmHg; P = 0.005) and lower diurnal variation in BP (11.8 +/- 4.6 vs. 14.2 +/- 4.2 and 14.8 +/- 4.3%; P = 0.011) compared with ID and II groups. Four patients in the DD group proved to be non-dipper compared with one in the ID and none in the II group (P = 0.026). Twenty-four-hour diastolic blood pressure was independently predictive for AER as dependent variable in the DD genotype patient group (r(2) = 0.12, P = 0.03). CONCLUSIONS: Children and adolescents with Type 1 diabetes do not differ from the non-diabetic population regarding the I/D polymorphism of the ACE gene. ACE gene polymorphism is associated with BP abnormalities in normotensive and normoalbuminuric children and adolescents with Type 1 diabetes.     

Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE

Systemic lupus erythematosus (SLE) is an inflammatory multisystem disease of unknown etiology with immunologic aberrations. Many studies have shown that genetic and environmental factors are implicated in the development of SLE. Angiotensin-converting enzyme (ACE) affects various immune phenomena through the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin II and inactivating bradykinin. We investigated the correlation between insertion/ deletion polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement and lupus nephritis. Two-hundred and eleven Korean patients fulfilling the ACR criteria and 114 healthy subjects were enrolled. The ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. The nephritis patients were classified by the WHO classification. In addition, the activity and chronicity index were used to assess the severity of renal involvement. We evaluated vascular involvement by the presence or absence of hypertension, Raynaud's phenomenon, livedo reticularis, antineutrophil cytoplasmic antibody and the SLICC/ACR Damage Index. The gene frequency of ACE gene polymorphism was as follows: II 39 vs 34%, ID 41 vs 50%, DD 20 vs 16% in SLE patients and controls, respectively. There was no difference in genotype frequency between both groups. There were no significant differences between the distribution of ACE gene genotypes and lupus nephritis and its related parameters, including WHO classification, activity index, chronicity index, renal dysfunction and amount of 24 h urinary protein. The ACE genotypes and alleles did not affect the presence of vascular manifestations evaluated, but the frequency of DD genotype was significantly low in SLE patients with Raynaud's phenomenon compared to those without Raynaud's phenomenon (P = 0.002 for ACE ID vs DD and II, OR 2.7, 95% CI 1.43-5.09; P=0.023 for ACE DD vs ID and II, OR 0.33, 95% CI 0.12-0.89). Also skewing from DD to II genotype was noted in patients with anti-Sm antibody compared to those without anti-Sm antibody (P = 0.025 for ACE DD vs ID and II, OR 0.21, 95% CI 0.05-0.93). The onset age of serositis was older in patients with the ID genotype than the others (ID= 34.5+/-10.8, II + DD = 25.6+/-10.2, P= 0.002). Also the onset age of malar rash was older in patients with II genotype than the others (II=26.7+/-8.4, ID+DD=21.3+/-9.0; P=0.021). The patients with I allele showed a significantly higher frequency of serositis (P = 0.022). Taken together, the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis and the vascular manifestations, including Raynaud's phenomenon, in Korean SLE patients, although the DD genotype was negatively associated with Raynaud's phenomenon among SLE patients. However, it would be valuable to evaluate the role of other genes potentially related to vascular events, such as endothelin, nitric oxide or angiotensin II receptor as well as ACE gene.     

Lower mortality in patients with the DD genotype of the angiotensin-converting enzyme gene after acute myocardial infarction.

OBJECTIVE: The angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with different serum ACE concentrations and cardiac ACE activity. We assessed whether the ACE gene I/D polymorphism influenced cardiac mortality in Japanese patients with acute myocardial infarction. METHODS AND RESULTS: The ACE gene I/D polymorphism was determined in 441 consecutive patients with a first myocardial infarction.There were 69 patients (16%) with the DD genotype, 194 patients (44%) with the ID genotype, and 178 patients (40%) with the II genotype. During a mean follow-up of 9.4 months, there were 49 cardiac deaths (DD, n = 4; ID, n = 26; II, n = 19).The DD genotype was significantly associated with a lower mortality than the other genotypes (p = 0.0363) by Cox regression analysis adjusted for age, sex, site of myocardial infarction, Killip functional class, reperfusion therapy during acute phase, ACE inhibitor use, and beta-blocker use. CONCLUSIONS: In a selected cohort of Japanese patients, the DD genotype was associated with a significantly lower cardiac mortality after a first myocardial infarction.     

Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis

OBJECTIVE: Systemic sclerosis (SSc) is characterized by microvascular and macrovascular alterations. The D allele of the ACE I/D polymorphism is known to be associated with an increased incidence of atherosclerosis and has been recently proposed as associated with increased risk of SSc. This study evaluates the relationship between intima-media thickness (IMT), ankle-brachial pressure measurements (ABPI) and ACE I/D polymorphism in SSc patients. METHODS: According to the presence of ACE D allele (analysed by PCR), 53 SSc patients (47 females and 6 males; median age was 60.4 +/- 10.68 yrs; range 40-75 yrs) were divided in carriers of the D allele (DD + ID) (n = 46) and carriers of the I allele (II) (n = 7). In these patients, IMT and ABPI [calculated as the posterior tibial artery pressure (mmHg) divided by the brachial pressure] were obtained. Forty-three healthy controls (40 women and 13 men; median age 56.3 +/- 10.23; range 40-70 yrs) of the same ethnicity were recruited. RESULTS: SSc patients had IMT significantly higher than controls (0.85 +/- 0.03 vs 0. 68 +/- 0.01; P < 0.03). No significant differences (P > 0.3) in ABPI values between patients (1.018 +/- 0.10) and controls (1.091 +/- 0.11) were found. SSc patients with ACE DD and ID genotype showed an IMT significantly greater (0.89 +/- 0.03) than those carrying the II genotype (0.61 +/- 0.01) (P < 0.04). ABPI was not different among ACE gene genotypes. CONCLUSION: Our findings confirm an increased prevalence of macrovascular disease in SSc patients and show that IMT is greater in patients carrying the ACE DD and ID genotype in comparison with II homozygotes. This suggests that, in SSc, the presence of ACE D allele may predispose to an involvement of the macrovascular system.     

性别因素对原发性高血压候选基因研究的影响作用

目的探讨研究样本中的性别因素对原发性高血压（EH）候选基因研究结果的影响。方法应用聚合酶链反应这一分子生物学研究方法,分析EH组患者及正常血压对照组（两组中男性女性人数相等）人群血管紧张素转换酶（ACE）基因插入／缺失（I／D）多态性,进而探讨性别比例对该类研究结论的可能影响。结果男性EH组DD基因型频率显著高于男性对照组（x^2=6．98,P=0．004）,D等位基因频率在男性EH组亦较男性对照组显著增高（x^2=6．87,P=0．009）,而ID和II基因型频率在男性EH组和男性对照组间差异无统计学意义（P〉0．05）。女性EH组与女性对照组比较,各基因型和等位基因频率分布差异均无统计学意义（P〉0．05）;男性EH组中的DD基因型分布比例与女性EH组中的DD基因型分布比例相比有显著统计学意义（x^2=4．06,P=0．044）。此外,EH组中男性DD型者的收缩压及脉压水平均显著高于ID型和II型者（P均〈0．05）,但舒张压在3种基因型间差异无统计学意义（P〉0．05）。同时,EH组II、ID基因型的男性的收缩压、舒张压、脉压差异均无统计学意义（P〉0．05）。女性患者中,各基因型间收缩压、舒张压及脉压的水平差异均无统计学意义（P〉0．05）。结论男性中的DD基因型成员与EH（尤其在收缩压、脉压）的关联可能比男性中的II、ID基因型以及所有的女性更为密切。性别可能作为一个混杂因素,对包括ACE基因I／D多态性在内的诸多EH候选基因与EH的相关性研究的结论产生影响。     

The association between angiotensin-converting enzyme gene polymorphism and coronary calcification. The Rotterdam Coronary Calcification Study

BACKGROUND: An insertion/deletion (I/D) polymorphism in the gene encoding angiotensin-converting enzyme (ACE) has been associated with serum ACE levels. The association between the ACE I/D polymorphism and coronary heart disease is unclear. Electron-beam-computed tomography (EBT) is a technique to non-invasively quantify the amount of coronary calcification. We investigated the association between the ACE I/D polymorphism and coronary calcification. METHODS AND RESULTS: The Rotterdam Coronary Calcification Study is a population-based study in subjects aged 55 years and over. EBT scanning was performed in 2013 participants. Coronary calcification was quantified according to the Agatston score. The ACE I/D polymorphism was available for 1976 subjects. Geometric mean calcium scores in men with the II, ID and DD genotype were 167, 207 and 219, respectively. However, the difference in calcium score (p=0.19 for ID versus II; p=0.15 for DD versus II) and the trend (ptrend=0.17) were not significant. Calcium scores in women with the II, ID and DD genotype were 44, 42 and 36, respectively. There were no significant differences in calcium score (p=0.78 for ID versus II; p=0.29 for DD versus II), neither was the trend (ptrend=0.27). After we stratified on cardiovascular risk factors, no associations were present. CONCLUSION: The present study failed to show an association between the ACE I/D polymorphism and coronary calcification in the general population. Also, no significant associations were present between the ACE I/D polymorphism and coronary calcification in strata of cardiovascular risk factors.     

Beta-adrenergic receptor blockade and the angiotensin-converting enzyme deletion polymorphism in patients with chronic heart failure

BACKGROUND: Beta-adrenergic receptor blockade is an established treatment of chronic heart failure (HF). Previous studies have suggested a potential pharmacogenetic interaction between beta-blocker therapy and the angiotensin-converting enzyme (ACE) I/D polymorphism in patients with HF. AIMS: We designed this study to analyze changes in myocardial function of HF patients in response to beta-blocker therapy as a function of the ACE I/D polymorphism. METHODS AND RESULTS: We studied 199 consecutive patients with chronic HF not treated with beta-blockers. Before initiation of beta-blockers and 3 months after the maximal tolerated dose was reached, patients underwent echocardiography, radionuclide angiography, and a cardiopulmonary exercise test. We extracted genomic DNA from white blood cells and determined the ACE I/D polymorphism. Thirty-five (18%) patients had the II genotype, 86 (43%) the ID genotype and 78 (39%) the DD genotype. A significant and similar improvement in left ventricular ejection fraction (LVEF) was observed in II (from 0.30+/-0.10 to 0.41+/-0.13; P<0.0001), ID (from 0.29+/-0.11 to 0.39+/-0.13; P<0.0001) and DD patients (from 0.31+/-0.11 to 0.40+/-0.13; P<0.0001). Peak Vo(2) before and after beta-blockade was similar among the three groups. The proportion of responders to beta-blockers (patients without cardiac events during titration who had an increase in LVEF >5% after beta-blockers) was similar among the three groups (II: 65.9%%, ID: 60.6%%, DD: 65.9%; P=NS). During a median follow-up of 933 days, there was no evidence for any effect of ACE I/D polymorphism on cardiac survival. CONCLUSIONS: We observed no evidence of pharmacogenetic interaction between the ACE I/D polymorphism and the effects of beta-blockade on LVEF and other prognostic parameters in patients with chronic HF. Our results support the initiation of beta-blockers in HF patients with the II or the ID genotype as well as in those with the DD genotype.     

Angiotensin converting enzyme gene insertion-deletion polymorphism is associated with juvenile rheumatoid arthritis

OBJECTIVE: To investigate the incidence of angiotensin converting enzyme (ACE) gene insertion-deletion (I/D) polymorphism genotypes in children with juvenile rheumatoid arthritis (JRA), a heterogeneous chronic disease with autoimmune pathology. ACE gene I/D polymorphism influences the plasma and tissue levels of ACE and has an involvement in inflammatory mechanisms. METHODS: The incidence of ACE gene I/D polymorphism genotypes was determined in 82 children with JRA from Kuwait and compared to that in 48 ethnically matched healthy controls using polymerase chain reaction. RESULTS: A considerably higher incidence of II genotype was observed in the JRA patients compared to controls (p < 0.003). In contrast, no statistically significant difference was detected in the incidence of DD and ID genotypes in JRA patients and controls (p = 0.276 and 0.460, respectively). The incidence of ACE gene polymorphism genotypes was also studied in clinical subclasses of JRA patients and controls. There was no significant difference in the incidence of DD and ID genotypes in either of the 3 JRA subclasses (oligoarticular, polyarticular, and systemic) when compared to controls. However, the incidence of II genotype was found to be significantly higher in all the 3 JRA subclasses compared to controls. The strongest association between II genotype and JRA subclasses was detected in systemic JRA, followed by oligoarticular and polyarticular JRA. This was also reflected in a higher prevalence of I-allele in the systemic JRA cases (13/26, 50%) compared to the D-allele (11/26, 42%). In contrast, D-allele of the ACE gene was more prevalent in oligoarticular and polyarticular JRA cases, than the I-allele (61% and 58%, respectively). CONCLUSION: Our data suggest a significant association of the I-allele of the ACE gene I/D polymorphism with the 3 clinical subclasses of JRA in children, and the highest association was observed in systemic JRA cases.     

冠心病与血管紧张素转换酶和内皮型一氧化氮合酶基因多态性及交互作用的临床研究

目的联合对冠心病患者血管紧张素转换酶（ACE）基因多态性和内皮型一氧化氮合酶（eNOS）基因G894T多态性进行分析,探讨基因多态性与冠心病的关系和交互作用及遗传学机制在冠心病发病及预后中的临床意义。方法应用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）分析技术检测236例冠心病患者及190例正常人ACE和eNOS两种基因多态性。同时测定血脂、血糖、体重指数（BMI）、左室射血分数（LVEF）和血压。结果冠心病组ACE基因DD型频率[36％（86／236）]显著高于对照组[19％（36／190）,P〈0．01],Ⅱ型频率[27％（64／236）]显著低于对照组[49％（93／190）,P〈0．05]。冠心病组DD型甘油三酯（TG）[（2．2±1．7）mmol／L]显著高于Ⅱ型TG[（1．6±0．8）mmol／L和ID型TG[（1．7±0．9）mmol／L,均P〈0．05],DD型高密度脂蛋白胆固醇[HDL—C（1．2±0．4）mmol／L]显著低于Ⅱ型HDL—C[（1．3±0．3）mmol／L,P〈0．05],DD型血糖[（6．2±1．7）mmol／L]和BMI[（25．7±2．8）kg／m^2]显著高于ID型[血糖：（5．6±1．3）mmol／L,BMI：（24．8±3．1）kg／m^2。,P〈0．05],DD型LVEF（56％±14％）显著低于Ⅱ型LVEF（62％±15％）和ID型LVEF（61％±14％）,均P〈0．05。收缩压、舒张压、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL—C）、糖尿病组与非糖尿病组、急性冠状动脉综合征组与非急性冠状动脉综合征组、单支病变组与多支病变组在ACE和eNOS基因不同基因型之间差异均无统计学意义。冠心病组eNOS基因GT型频率[28％（67／236）]显著高于对照组[17％（32／190）,P〈0．01],GG型频率与对照组比较,差异无统计学意义。TG、HDL—C、血糖、BMI和LVEF在eNOS基因不同基因型之间差异均无统计学意义（均P〉0．05）。携带DD型患冠心病的概率是携带Ⅱ型的1．74倍（P〈0．01）,携带GT型患冠心病的概率是携带GG型的1．73倍（P〈0．05）。两种基因对患冠心病的交互作用显示为如同时携带Ⅱ型和GG型,患冠心病的概率是37．9％,而同时携带DD型和GT型患冠心病的概率是77．8％。结论ACE基因多态性和eNOS基因多态性与冠心病及某些危险因素显著相关,同时携带DD型和GT型两种易患基因型时,患冠心病的概率明显增加,具有显著的遗传倾向。     

Angiotensin-converting enzyme gene polymorphism and microvascular complications in Turkish type 2 diabetic patients

The aim of this study was to investigate whether an association exists between the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and microvascular complications of type 2 diabetes mellitus in Turkish patients. A total of 239 type 2 diabetic patients and 138 sex and age matched control subjects were included into the study. The I/D polymorphism was determined by polymerase chain reaction (PCR). Nephropathy status was determined according to urinary albumin/creatinine ratio (microg/mg) (<30 normoalbuminuria, 30-300 microalbuminuria, >300 macroalbuminuria) and retinopathy was evaluated by fundoscopic examination and by flourescein fundus angiography. The distribution of ACE I/D polymorphism and allele frequencies in diabetic patients were not significantly different from controls, DD genotype 32.2 versus 37.2%; ID genotype 50.6 versus 47.1%; and II 17.2 versus 15.2%; D allele 57.5 versus 61.2%; I allele 42.5 versus 38.8%. Genotype distribution between normo-, micro- and macroalbuminuric patients did not differ significantly (DD:ID:II (%), normoalbuminuria, 35:46:19; microalbuminuria, 28:55:17; macroalbuminuria, 31:55:14). There was also no difference in genotype distribution between patients with and without retinopathy (DD:ID:II (%), retinopathy positive, 32:51:17; retinopathy negative, 33:49:18). In conclusion, the ACE I/D polymorphism does not seem to be associated with diabetic nephropathy and retinopathy in Turkish type 2 diabetic patients.     

Insertion/Deletion Polymorphism of the Angiotensin I-Converting Enzyme Gene Is Associated With Coronary Artery Plaque Calcification As Assessed by Intravascular Ultrasound

Objectives. We evaluated the influence of the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene on coronary plaque morphology and calcification in patients with angiographically documented coronary artery disease (CAD).Background. The ACE I/D polymorphism has been associated with an increased risk of myocardial infarction in patients with the DD genotype but not with the presence of native CAD.Methods. We studied 146 patients undergoing percutaneous transluminal coronary angioplasty for stable angina pectoris by means of preinterventional intravascular ultrasound (IVUS). Qualitative and quantitative criteria were used to classify the target lesions as poorly or highly echoreflective or as calcified. Genomic deoxyribonucleic acid was analyzed by polymerase chain reaction (PCR) to identify the I/D polymorphism, with a second insertion-specific PCR in DD genotypes to prevent mistyping.Results. The ACE genotype groups (DD 46, ID 68, II 32) were well matched for the basic characteristics. Patients with the DD genotype had significantly more calcified lesions (DD 80%, ID 57%, II 66%; unadjusted odds ratio [OR] 2.88, 95% confidence interval [CI] 1.30 to 6.92, p = 0.008) and more calcifications >180° of the vessel circumference (DD 22%, ID 10%, II 6%; OR 2.80, 95% CI 1.05 to 7.63, p = 0.03). The prevalence of myocardial infarction was not significantly associated with coronary calcification (OR 1.44, 95% CI 0.72 to 2.88, p = 0.31).Conclusions. Patients with CAD and the ACE DD genotype have a significantly higher incidence and greater extent of coronary lesion calcification, as determined by IVUS. This finding indicates that the ACE I/D gene polymorphism is related to the development or progression of atherosclerotic plaque calcification.     

血管紧张素转化酶基因多态性对血清血管紧张素转化酶水平及血脂的影响

为探讨血管紧张素转化酶基因多态性对本地人群高血压患者和正常人血清血管紧张素转化酶及血脂水平的影响,采用聚合酶链反应技术,对118例高血压患者和98例正常人的血管紧张素转化酶基因插入/缺失多态性进行分型,并检测血清血管祭张素转化酶活性及血脂含量。结果发现,高血压组血管紧张素转化酶三种基因型(缺失纯合子型、插入纯合子型和杂合子型)及插入/缺失等位基因的频率与正常对照组比较差异无统计学意义(X2=0.468,P=0.791;X2=0.379,P=0.538)。血清血管紧张素转化酶活性在三种基因型之间差异有显著性意义(F=17.107,P=0.000)。高血压组总胆固醇、低密度脂蛋白胆固醇、脂蛋白(a)高于正常对照组(P<0.05);高血压组三种基因型之间血脂各指标含量及正常对照组三种基因型之间总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和载脂蛋白B含量差异有显著性意义(P<0.05)。此结果提示,血管紧张素转化酶基因多态性与血清血管肾张素转化酶活性及血脂含量有关,缺失纯合子型高血压患者血清血管紧张素转化酶活性最高且易患高脂血症。     

Polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation.

BACKGROUND: The angiotensin-converting enzyme (ACE) deletion allele, ACE D, is associated with increased ACE activity and adverse outcomes in cardiovascular disease. Although activation of the renin-angiotensin-aldosterone system (RAAS) now appears to play a role in the pathophysiology of atrial fibrillation (AF), it remains to be determined if ACE genotype impacts response to conventional AAD therapy in patients with AF. OBJECTIVES: The purpose of this study was to investigate whether response to antiarrhythmic drug (AAD) therapy in patients with AF is modulated by the ACE I/D polymorphism. METHODS: We studied 213 patients (147 men, 66 women; ages 52 +/- 15 years) prospectively enrolled in the Vanderbilt AF Registry. AAD therapy outcome was defined prospectively as response if there was a >or=75% reduction in symptomatic AF burden or nonresponse if AF burden was unchanged, necessitating a change in drugs or therapy. RESULTS: Lone AF (age <65 years, no identifiable cause) was present in 72 (34%) patients, whereas hypertension was the most common underlying disease in the remaining 141 (41%). AF was paroxysmal in 170 (80%) and persistent in 43 (20%). The frequencies of the DD, ID, and II genotypes were in Hardy-Weinberg equilibrium. Lone AF and DD/ID genotypes were highly significant predictors of failure of drug therapy (P <.005). In patients with lone AF, failure of drug response was 5%, 41%, and 47% in patients with II, ID, and DD genotypes, respectively, (P <.005, II vs. ID/DD). CONCLUSIONS: These results provide further evidence for a role of RAAS activation in the pathophysiology of AF and point to a potential role for stratification of therapeutic approaches by ACE genotype.     

Association of the angiotensin-converting enzyme gene polymorphism with chronic heart failure in Chinese Han patients

BACKGROUND: An insertion/deletion (I/D) polymorphism is present in the 16th intron of the angiotensin-converting enzyme (ACE) gene and is associated with serum and tissue ACE level. Some studies have shown that the DD genotype is associated with some cardiovascular diseases; while ACE polymorphism's effect on chronic heart failure (CHF) remains uncertain. AIM: To investigate the association of the ACE gene I/D polymorphism with CHF in the Chinese Han population. METHODS: The genotype was determined by polymerase chain reaction in 102 normal controls and in 79 patients with CHF. Plasma angiotensin (Ang) levels were assessed by radio-immunity assay. Left ventricular end-diastolic diameters (LVDD) and left ventricular ejection fractions were assessed by echocardiography. RESULTS: The ACE gene polymorphism distribution was similar in patients and control subjects. However, ACE gene DD polymorphism was associated with a more severe condition, greater LVDD [mm: DD: 71+/-7, ID: 62+/-5, II: 60+/-5, P<0.001 DD vs. ID, P<0.001 DD vs. II] and higher plasma Ang II level [pg/ml DD: 92+/-19, ID: 79+/-21, II: 65+/-17 P<0.05 DD vs. ID, P<0.001 DD vs. II]. CONCLUSION: In Chinese Han patients with CHF, ACE gene DD polymorphism might be a marker of a more severe condition, and a higher level of activation of the renin-angiotensin system.     

I/D gene polymorphism of the angiotensin-converting enzyme and left ventricular hypertrophy. Response to converting enzyme inhibitors

BACKGROUND: The present study was designed to assess whether the angiotensin-converting enzyme (ACE) gene I/D polymorphism influence the ACE inhibitors effect on the regression of left ventricular hypertrophy. METHODS: Sixty hypertensive subjects never treated by antihypertensive drugs, aged 46 +/- 11 years, were included in the study. Follow-up with ACE inhibitor treatment was 60 +/- 26 months. Genotypes for ACE I/D polymorphism (DD, ID or II) were determined by PCR. The left ventricular mass index (LVMI) was assessed by two-dimensional directed M-mode echocardiography. RESULTS: ACE genotype distribution was in agreement with the Hardy-Weinberg equilibrium: 21 patients had the DD genotype, 29 were ID, and 10 were II. At baseline, age, systolic arterial pressure and LVMI didn't differ on the basis of genotype. Body mass index was significantly higher in II than in ID and DD groups. Regression of LVMI with ACE inhibitor treatment was similar in the 3 genotypes (-8.9%, -0.6%, -12.1% in DD, ID and II groups respectively). In addition, decrease of systolic arterial pressure was identical in 3 groups. CONCLUSION: ACE gene I/D polymorphism seems not to influence regression of left ventricular hypertrophy by ACE inhibitors in essential hypertension.     

Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure

OBJECTIVES: We evaluated the interaction of angiotensin-converting enzyme (ACE) inhibitor therapy with the effect of the ACE D/I polymorphism on heart failure survival. BACKGROUND: The ACE deletion allele, ACE-D, is associated with increased ACE activity. The utilization of ACE genotyping to predict the impact of ACE inhibitor dose has not been previously evaluated. METHODS: We prospectively studied 479 subjects with systolic dysfunction (left ventricular ejection fraction 0.25 +/- 0.08). Subjects were divided on the basis of ACE inhibitor therapy into low dose (50%, n = 201), or those receiving angiotensin receptor antagonists (n = 51). Patients were genotyped for the ACE D/I polymorphism, followed to the end point of death or cardiac transplantation, and transplant-free survival compared by genotype. RESULTS: The ACE-D allele was associated with an increased risk of events (p = 0.026). In analysis by ACE inhibitor dose, this effect was primarily in the low-dose group (1-year percent event-free survival: II/ID/DD = 86/77/71,2-year = 79/66/59, p = 0.032). In the standard-dose group, the impact was markedly diminished (1-year: II/ID/DD = 91/81/80, 2-year: 77/70/71, p = 0.64). The impact of beta-blockers and high dose ACE inhibitors was greatest in subjects with the ACE DD genotype (p = 0.001) and was less apparent with the II and ID genotypes (p = 0.38). CONCLUSIONS: Higher doses of ACE inhibitors diminished the impact of the ACE-D allele, and the benefits of beta-blockers and high-dose ACE inhibitors appeared maximal for DD patients. Determination of ACE genotype may help target therapy for patients with heart failure.     

Angiotensin I-converting enzyme insertion/deletion polymorphism and cardiac mortality and morbidity after coronary artery bypass graft surgery

STUDY OBJECTIVES: This study was designed to evaluate whether the insertion (I)/deletion (D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is associated with mortality and cardiac morbidity after coronary artery bypass graft surgery (CABG). METHODS AND RESULTS: The ACE I/D genotype was determined in 249 consecutive patients who underwent CABG. Follow-up information (after 2 years) was obtained in 247 patients (99.2%). The primary end point was total mortality; the secondary end point was mortality from cardiac reasons, or the need for myocardial revascularization (coronary angioplasty or recurrent CABG) during follow-up. At follow-up, total mortality was 9.7% (all patients). None of the 51 patients with the ACE II genotype, 14 of 125 patients with the ACE ID genotype (11.2%), and 10 of 71 with the ACE DD genotype (14.1%) died during follow-up (p < 0.05). The ACE DD genotype, older age, diabetes mellitus, decreased left ventricular ejection fraction, and lack of internal mammary artery graft were independently related to an increased mortality after CABG. The incidence of the secondary end point was 14.5% (all patients): ACE II, 5.8%; ACE ID, 9.4%; ACE DD, 30.3% (p < 0.05). The ACE DD genotype and the presence of a left main coronary artery stenosis >or= 50% were independent predictors for the secondary end point. CONCLUSION: The ACE DD genotype is associated with increased midterm mortality and cardiac morbidity after CABG.     

Angiotensin-converting enzyme gene polymorphism influences degree of left ventricular hypertrophy and its regression in patients undergoing operation for aortic stenosis.

Insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with increased left ventricular hypertrophy (LVH) in patients with cardiomyopathy and congestive heart failure. Patients with aortic stenosis (AS) have varying degrees of LVH at a given valve area. The aim of this study was to examine the relation between ACE gene polymorphism and the degree of LVH in patients undergoing operation for AS. Eighty-two patients who underwent operation for AS with a stentless valve were followed prospectively with echocardiographic assessments of left ventricular mass index (LVMI). ACE gene polymorphism was determined by polymerase chain reaction. The genotype (DD, ID, and II) frequency was the same as in healthy controls. The pressure difference across the aortic valve did not differ between genotypes. Patients with the DD genotype of the ACE gene had a higher LVMI (197 +/- 47 g/m2) preoperatively than those with ID (175 +/- 41 g/m2) or II (155 +/- 43 g/m2) genotypes (p = 0.01). LVMI decreased significantly in DD (p <0.001) and ID (p <0.001) genotypes but not in the II genotype during follow-up (mean 15 months). There was a significant difference in regression of LVMI over time between genotypes (p = 0.0056), with no significant difference between genotypes at follow-up. The DD genotype of the ACE gene is associated with increased preoperative LVH in patients treated surgically for AS. The DD genotype appears to be an important factor which increases hypertrophic myocardial reactivity to pressure overload.     

Angiotensin-Converting Enzyme Gene Polymorphism and Plasminogen Activator Inhibitor 1 Levels in Subjects with Cerebral Infarction

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.     

Lack of association between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and vasospastic angina

Background and hypothesis: 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 atherosclerosis and myocardial infarction, but its relation to vasospastic angina has not been fully proven. In the present study, we investigated the possible relationship between the ACE I/D genotype and vasospastic angina. Methods: We explored the distribution of the ACE genotype in 20 patients with vasospastic angina without fixed coronary artery stenosis, 55 angina patients with fixed coronary artery stenosis, and 30 control subjects without coronary artery disease. Results: The frequency of the DD genotype in patients with vasospastic angina (DD: 30.0%, ID: 20.0%, II: 50.0%) did not differ from that in the control subjects (DD: 23.3%, ID: 26.7%, II: 50.0%), while the frequency in patients with coronary artery stenosis (DD: 43.7%, ID: 21.8%, II: 34.5%) was significantly higher than that in the control subjects. The frequency of the D allele also did not differ between patients with vasospastic angina (0.40) and control subjects (0.37), while the frequency was significantly higher in patients with coronary artery stenosis (0.55). Conclusions: These findings suggest that the ACE DD genotype is a potent genetic risk factor for organic coronary artery disease, while it confers no appreciable increase in risk of vasospastic angina. These results also suggest the diversity of the pathogenesis of vascular lesions in these two types of coronary artery disease.