Angiotensin-converting Enzyme DD Genotype Research Articles

Deletion polymorphism of the angiotensin converting enzyme gene predicts persistent proteinuria in Henoch-Schönlein purpura nephritis

OBJECTIVETo study the influence of deletion/insertion polymorphism in the 16th intron of the angiotensin converting enzyme (ACE) gene on clinical manifestations of Henoch-Schönlein purpura nephritis.STUDY DESIGNCross sectional study. ACE gene...

Interethnic Differences in Coronary Heart Disease Mortality in 25 Populations: Association with the Angiotensin-Converting Enzyme DD Genotype Frequency

Despite changes in dietary habits and steadily increasing serum cholesterol concentrations, coronary heart disease (CHD) mortality rates in developed South-East Asian populations are still one quarter those in many Western populations. We propose that genetic factors may, in part, contribute to these differences in CHD mortality. Using an ecological study design, we have investigated the comparative roles of serum cholesterol concentration and the angiotensin-converting enzyme (ACE) homozygote deletion (DD) genotype frequency, which has recently been implicated in CHD mortality. Using our genotyping data from local Chinese populations, together with previously published data on ACE gene frequency and cholesterol concentrations, we correlated ACE DD genotype frequencies and mean serum cholesterol concentrations with World Health Organization age-adjusted CHD mortality rates in 25 ethnically diverse populations. Although mean serum cholesterol accounted for 67% of the variance in CHD mortality rates for all populations (r=0.82, 95% Cl 0.63-0.92, n=25, P<0.001), the ACE DD frequency accounted for 61% of the variance in 'low' cholesterol populations (r=0.78, 95% Cl 0.43-0.91, n= 14, P<0.001) with no additional contribution from serum cholesterol concentration. Moreover, in the 'low' cholesterol population, mean serum cholesterol accounted for only 37% of the variance. We hypothesize that differences in the frequency of the ACE DD genotype in populations with low mean serum cholesterol concentrations may play some part in determining interethnic differences in CHD mortality rates.

Interethnic differences in coronary heart disease mortality in 25 populations: association with the angiotensin-converting enzyme DD genotype frequency

Interethnic differences in coronary heart disease mortality in 25 populations: association with the angiotensin-converting enzyme DD genotype frequency

Association between angiotensin I-converting enzyme genotypes, extracranial artery stenosis, and stroke

The insertion(I)/deletion(D) polymorphism of the angiotensin-converting-enzyme (ACE) gene has been associated with an increased risk of myocardial infarction, lacunar stroke, and with an increased intimal-medial thickness in several populations. The aim of this study was to evaluate whether the ACE I/D genotype is associated with stenosis of extracranial arteries and stroke in middle-aged and aged men and women. We studied 388 patients (247 male, 141 female) using Doppler and Duplex ultrasound of the extracranial arteries. Patients' history was obtained by standard questionnaire and by the hospital case records. Genomic DNA was analyzed by polymerase chain reaction (PCR) to identify the I/D polymorphism, with a second insertion specific PCR in samples classified as homozygous DD genotypes to prevent mistyping. The ACE genotype groups (DD 132, ID 164, II 92) were well matched for the basic characteristics. The DD genotype was more common in patients with extracranial artery stenosis ≥50% compared with patients without stenosis (59/147 versus 73/241, odds ratio 1.54, 95%-CI 1.01–2.37), but was not associated with a history of stroke (30/91 versus 102/297, odds ratio 0.94, 95%-CI 0.57–1.54). The association of the DD genotype with extracranial artery stenosis was also present in hypertensive subjects ( n=206, odds ratio 1.76, 95%-CI 0.99–3.17). In the whole group multiple logistic regression analysis revealed that the association of the DD genotype with extracranial artery stenosis was independent of age, gender, hypertension, hyperlipidemia, and diabetes. In conclusion, the ACE DD genotype is a weak risk factor for hemodynamically relevant stenosis of extracranial arteries, but not for stroke.

Endothelial cell damage and angiotensin-converting enzyme insertion/deletion genotype in elderly hypertensive patients

Objectives. The purpose of this study was to investigate the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotype and endothelial cell dysfunction or hypercoagulable state in elderly hypertensive patients.Background. Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was recently reported to be associated with various cardiovascular diseases. However, the precise mechanism of this association remains unknown, and some confounding factors might also affect the association. Endothelial cell dysfunction and coagulation activation play important roles in both the atherosclerotic process and the onset of cardiovascular events.Methods. We identified the ACE I/D genotype and measured the plasma levels of markers of endothelial cell damage (von Willebrand factor [vWF] and thrombomodulin) and of coagulation activation (prothrombin fragment F1 + 2 [F1 + 2]) in 318 asymptomatic elderly patients with hypertension, aged 59–93 years.Results. The vWF level was significantly higher in those with the DD genotype (n = 54) than in those with the II genotype (n = 131, p < 0.0001) or with the ID genotype (n = 133, p < 0.0001). The TM levels were also higher in patients with the ID genotype (p < 0.005) and the DD genotype (p < 0.01) than in those with the II genotype. There were no differences in F1 + 2 level among the groups. Positive correlations of systolic blood pressure with levels of both vWF and thrombomodulin were found predominantly in patients with the II genotype (both p < 0.001), but no correlation was noted in those with the DD genotype.Conclusions. Considering the increased plasma levels of both endothelial cell-derived markers in the hypertensive patients with ACE DD genotype, we speculate that the ACE D allele is a risk factor for the development of hypertensive cardiovascular disease associated with endothelial cell damage.

Relation between severity of coronary artery disease, left ventricular function, and myocardial infarction, and influence of the ACE I/D gene polymorphism

Left ventricular (LV) systolic function is partly determined by severity of coronary artery disease and is improved by angiotensin-converting enzyme (ACE) inhibition, at least in post-infarct patients. Because the ACE insertion/deletion (I/D) gene polymorphism is associated with circulating and tissue ACE activity, we sought to evaluate the role of this genetic variant on LV function in patients studied with coronary angiography, taking into account coronary vessel anatomy and history of infarction. Coronary artery disease extent scores, coronary artery patency, and LV ejection fraction were assessed in 400 consecutive Caucasian patients referred for established or suspected ischemic heart disease. A previous infarction had occurred in 141 patients an average of 3.7 years before the study. The ACE DD genotype, compared with the ACE ID/II genotype, was associated with a 2.7% higher ejection fraction in noninfarct patients (p = 0.047) but a 5.0% lower ejection fraction in post-infarct patients (p = 0.047). An interaction effect between the ACE I/D gene polymorphism, the infarction status, and LV ejection fraction was observed in the whole population (p = 0.003), in patients with no disease and 1-, 2-, and 3-vessel diseases (p = 0.03 and p = 0.06, respectively), and in those with chronically occluded coronary vessels (p = 0.02). The influence of the ACE I/D gene polymorphism on LV function is modulated by infarction status and coronary anatomy.

Angiotensin converting enzyme gene I/D polymorphism in essential hypertension and nephroangiosclerosis

An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene significantly influences circulating ACE levels and plays a role in the development of target organ damage, that is, left ventricular hypertrophy in essential hypertension (EH), and microalbuminuria in diabetes mellitus. We have examined the role of the I/D polymorphism in essential hypertensive patients with renal involvement. The study was divided in two independent protocols. In protocol 1, we retrospectively analyzed the ACE genotypes in 37 essential hypertensive patients with a clinical and histopathological diagnosis of nephroangiosclerosis. In protocol 2, ACE genotypes as well as microalbuminuria and renal hemodynamic parameters were investigated in 75 patients with EH with normal renal function and a strong family history of hypertension. As control group, 75 healthy subjects with BP < 130/85 mm Hg and no family history of cardiovascular diseases were studied. The ACE variants were determined by PCR and the genotypes were classified as DD, DI and II. In protocol 1, patients with nephroangiosclerosis displayed a significant difference in the genotype distribution (57% DD, 27% DI, 16% II) when compared to the control population (25% DD, 64% DI, 11% II; P < 0.001). There was no significant difference in genotype distribution between hypertensive patients with normal renal function (protocol 2; 33% DD, 59% DI, 8% II) and the control group. There were no differences in age, blood pressure, microalbuminuria and duration of the disease among the three genotypes in the EH group from protocol 2. Taken together, these findings suggest that the DD genotype of ACE is associated with histopathologic-proven kidney involvement in patients with EH and that this polymorphism could be a potential genetic marker in hypertensives at risk of renal complications.

Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia.

Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene polymorphism increases the risk of myocardial infarction (MI). Studies have suggested that the ACE DD genotype is associated with increased plaque instability. We hypothesized that the ACE DD genotype may increase the risk of myocardial infarction and coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH) or familial defective apolipoprotein B-100 (FDB) who, as a group, are at high risk of having lipid-rich plaques in their coronary arteries. We determined the ACE genotypes and incidence of MI or surgical intervention for CHD in 213 adult patients with heterozygous FH or FDB. The incidence of MI in 35 male patients who carried the ACE DD genotype was 2.5 times that observed in male patients with the II or DI genotypes, and the incidence of CHD in male patients with the DD genotype was 2.2 times higher than in those who had ACE DI+II. The potential effects of ACE genotype on CHD could not be directly compared in female patients because of a disparity in the smoking history of the genotypic groups. From logistic regression analysis, the estimated odds ratio associated with the ACE DD genotype was 2.57 for MI and 2.21 for CHD adjusted for age, sex, and smoking history. The ACE DD genotype is associated with an increased risk of MI and CHD in patients with heterozygous FH or FDB. Determination of the ACE genotype in asymptomatic FH and FDB patients provides an additional means to identify those patients at greatest risk for the premature development of CHD.

Lack of association between the insertion/deletion polymorphism of the angiotensin-converting-enzyme gene and diabetic nephropathy in IDDM patients.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting-enzyme (ACE) gene has been reported to be associated with diabetic nephropathy in IDDM. We studied the relationship between this polymorphism and diabetic nephropathy in 210 IDDM patients. Their DNA was analyzed by polymerase chain reaction to type for the presence (I) or absence (D) of the 287 bp fragment in intron 16 of the ACE gene. The relative frequency of the different genotypes was 33.8% (DD), 43.8% (ID), and 22.4% (II). There were no significant differences between the genotypes in age, body-mass-index, blood pressure, plasma total cholesterol and triglycerides. The prevalence of microalbuminuria or nephropathy was 23.9% in the DD, 16.3% in the ID, and 17% in the II genotypes. The higher percentage of microalbuminuria or nephropathy in the DD genotypes was due to an increasing frequency of DD genotypes in the IDDM patients with long diabetes duration. After matching for diabetic retinopathy, gender, and diabetes duration, there was no association between the ACEI/D polymorphism and diabetic nephropathy. In conclusion, these results suggest that the ACE DD genotype cannot be regarded as a risk factor for diabetic nephropathy, but may even be associated with diabetes duration and thus longevity in IDDM patients.

Angiotensin-Converting Enzyme Genotypes and Risk for Myocardial Infarction in Women

Objectives. We tested for an association between the angiotensin-converting enzyme (ACE) DD polymorphic genotype and myocardial infarction (MI) in a sample group composed exclusively of women.Background. The human ACE gene occurs with either an insertion (I allele) or a deletion (D allele) of a 287-base pair (bp) Aluelement. Part of the variance in serum ACE levels may be accounted for by this polymorphism. Also, the DD genotype has been associated with an increased risk of MI in predominantly male populations. However, the risk in women is poorly defined.Methods. Genomic DNA was extracted from buffy coat blood using a phenol/chloroform method. Angiotensin-converting enzyme alleles were identified using primers to bracket the insertion region in intron 16. Amplification using polymerase chain reaction allowed identification of a 490-bp (I allele) or a 190-bp (D allele) product, or both.Results. Allelic and genotypic frequencies in control subjects were similar to those reported in mostly male populations, and frequencies of genotypes were in the Hardy-Weinberg equilibrium. In contrast, the distribution of genotypes in patients with MI diverged from the equilibrium. Specifically, DD genotypic frequency was increased in women with (n = 141) versus without (n = 338) a previous MI (39% vs. 29%, odds ratio [OR] 1.54, 95% confidence interval 1.02 to 2.32, p < 0.04). Risk was particularly increased in women <60 years old (OR 2.04, p < 0.05). In contrast, the DD genotype did not predict angiographic coronary artery disease.Conclusions. Consistent with findings in male-dominated populations, a modest association of the ACE DD genotype with MI was found in women. The basis for this association requires further study.

The Angiotensin Converting Enzyme DD Genotype Is Associated With a Decreased Response to Angiotensin II in Human Arteries

The Angiotensin Converting Enzyme DD Genotype Is Associated With a Decreased Response to Angiotensin II in Human Arteries

The angiotensin converting enzyme DD genotype is associated with a decreased response to angiotensin II in human arteries

The angiotensin converting enzyme DD genotype is associated with a decreased response to angiotensin II in human arteries

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

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. 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. 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). 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.

The angiotensin-converting enzyme gene and the angiotensin II type I receptor gene as candidate genes for microalbuminuria. A study in nondiabetic and non-insulin-dependent diabetic subjects.

Familial clustering of microalbuminuria with cardiovascular disease suggests a possible common genetic antecedent. We have tested the hypothesis that the angiotensin-converting enzyme (ACE) DD genotype and the angiotensin II type I receptor (AT1R) gene C allele represent the common link between microalbuminuria and coronary heart disease. The frequency of polymorphisms of the ACE and AT1R genes were investigated in 509 nondiabetic white subjects and in 86 non-insulin-dependent diabetic white patients. There was no significant difference in albumin excretion rate between the genotypes in nondiabetic subjects on either a daytime or an overnight sample or in diabetic subjects expressed as a normalized albumin concentration on an untimed morning urine collection. We have found no evidence for an association between polymorphism of the ACE or AT1R genes and microalbuminuria in two groups of subjects without insulin-dependent diabetes.

Angiotensin-converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus and its relationship with diabetic nephropathy

Previous studies have shown that the angiotensin-converting enzyme (ACE) gene polymorphism is associated with an increased risk of vascular disease in non-diabetic patients. The present study was conducted on 509 NIDDM patients who underwent a screening test to determine their ACE genotype for the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Various baseline indices were correlated with the three ACE polymorphisms. The genotype was determined through polymerase chain reaction amplification of the angiotensin-converting enzyme polymorphism. The univariate relationship between the presence of the DD genotype with nephropathy as measured by urinary albumin excretion (UAE), and a history coronary artery disease (CAD) was then examined. Finally, a multiple model for each UAE and CAD was created so as to determine the independent effects of the presence of the DD genotype on each diabetic complication. Univariately, the presence of the DD genotype was associated with diabetic nephropathy. Furthermore, in a multiple model predicting diabetic nephropathy, the presence of the DD genotype was independently associated with diabetic nephropathy (odds ratio = 2.8, 95% confidence interval 1.4 to 5.5) but not CAD. Thus, the ACE DD genotype in 509 non-Hispanic white NIDDM patients in a metropolitan area in the U.S. was independently associated with the presence of diabetic nephropathy and, therefore, may be potentially used as a marker for NIDDM patients at risk for developing diabetic nephropathy.

Hypertensive nephropathy and the gene for angiotensin-converting enzyme.

To investigate the genetic determinants for microalbuminuria, we studied an insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene, which influences the plasma ACE level, in 333 consecutive hypertensive patients and 113 normotensive control subjects. The urinary albumin excretion rate was calculated by using a 12-hour urine collection (mean for two consecutive nights from 7 PM to 7 AM) in all 333 hypertensive patients. The ACE D allele frequency did not differ significantly between the hypertensive patients and the normotensive control subjects (0.37 and 0.33, respectively). Among the hypertensive patients, nephropathy (microalbuminuria and albuminuria) was more common (P < .001) in those with the ACE DD genotype than in those with other genotypes. The D allele frequency in the nephropathy group was significantly higher than that in the normoalbuminuric group (0.45 versus 0.32, chi 2 = 10.8, P < .001). These results indicate that ACE I/D polymorphism is a genetic determinant for hypertensive renal disease in hypertensive patients. This polymorphism might be a confounding factor involved in the association between hypertensive nephropathy and cardiovascular events.

Relationship of polymorphisms in the renin-angiotensin system and in E-selectin of patients with early severe coronary heart disease.

Previous association studies between angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) polymorphisms and several cardiovascular diseases have reported variable results. Therefore we examined the association of the DNA variants of ACE and AGT with early, severe coronary heart disease (CHD). In addition, we compared the genotypes of both polymorphisms and the recently discovered polymorphism in the E-selectin gene in both patients and an unselected population. This study included 113 patients with severe CHD (50 years old or less) and up to 197 control subjects. The frequencies of the ACE I/D variants were 48% I and 52% D in the controls and 46% I and 54% D in the patients. The frequencies of the AGT-M235T polymorphism were 60.8% M and 39.2% T in controls and 49.1% M and 50.9% T in the patients. The frequencies of the S128R polymorphism of the E-selectin were 91.3% S and 8.7% R in controls and 84.5% S and 15.5% R in the patients. In our studies the DD genotype of ACE was not associated with early severe CHD. We found a correlation between the M235T molecular variant of AGT and the S128R variant of E-selectin to early severe CHD.

Associations between candidate loci angiotensin-converting enzyme and angiotensinogen with coronary heart disease and myocardial infarction: The NHLBI family heart study

Angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) are major components of the renin-angiotensin systems. An association between myocardial infarction (MI) and the ACE DD genotype of the insertion/deletion (ID) polymorphism in intron 16 of the ACE gene has been reported. However, other similarly designed studies have not found such an association. Angiotensin II, the product of AGT, has a direct effect on vascular tone; and a variant in the AGT gene has been found to be associated with MI in the Japanese. This case-control study was initiated to investigate whether the ACEI/D and AGT M235T polymorphisms are associated with an increased risk for coronary heart disease (CHD) and MI. Our study groups were composed of participants in the National Heart Lung Blood Institute (NHLBI) Family Heart Study (FHS) selected from three population-based studies: two Atherosclerosis Risk in Communities (ARIC) centers (Forsyth County, NC, and Minneapolis, MN), and the Framingham Heart Study. In multivariate analysis within ARIC Caucasians, a significant positive association was found between CHD (controls = 230, cases = 232) and the AGT TT genotype (P = 0.022; OR = 1.84, 1.09–3.10 95% CI). When we restricted the analysis to a low-risk group for CHD (controls = 70, cases = 35) an interaction between the ACE DD and AGT TT genotypes was significant (P = 0.025; OR = 5.02 1.22–20.6 95% CI). After further subsetting low-risk cases to those with a definite MI (controls = 74, cases = 16), we found that the association with the ACE DD genotype was also significant (P = 0.013, OR = 3.94, 1.28–12.2 95% CI). Comparable tests in the Framingham sample failed to support an association of these markers with CHD. In conclusion, within selected groups the ACE D and AGT 235T alleles are statistically associated with CHD and MI, and there is a synergistic interaction between the two alleles. These results and those from previous studies together suggest that the association of these two loci is neither strong nor consistent and involves a complex interaction among risk factors and genotypes.

High frequency of a deletion polymorphism of the angiotensin-converting enzyme gene in asthma

Background: An insertion-deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been shown to be associated with levels of ACE. Because ACE is heavily expressed in the lungs and plays a key role in the metabolism of angiotensin II and bradykinin, which are potentially involved in the pathogenesis of asthma, we tested the hypothesis of an association between the polymorphism of the ACE gene and asthma. Methods: Seventy-nine patients with asthma, 54 healthy subjects, and 33 patients with nonasthmatic lung disease were studied. Pulmonary function tests were performed in patients with asthma, and the ACE genotypes were determined in all subjects by the polymerase chain reaction. Results: The ACE genotype distribution was similar in healthy subjects and in patients without asthma. By contrast, the population of patients with asthma was characterized by a higher prevalence of the DD genotype of ACE (odds ratio, 2.09; 95% confidence interval, 1.05 to 4.16; p = 0.023). No difference in pulmonary function test results was detected in asthmatic patients according to the distribution of ACE genotypes. Conclusion: This study reports an association between the DD genotype of ACE and asthma, which is not related to the degree of airway obstruction. These results need to be confirmed by a larger case-control study. (J Allergy Clin Immunol 1997;99:53-7.)

Angiotensin-Converting Enzyme and Heart Chymase gene Polymorphisms in Hypertrophic Cardiomyopathy

We examined the insertion/deletion polymorphism in the angiotensin-converting enzyme gene and identified polymorphisms in the heart chymase gene to test the hypothesis that these angiotensin II-producing enzymes are associated with a monogenic cardiac disease (50 patients and 50 control subjects) as a model of cardiac hypertrophy. We found that the angiotensin-converting enzyme DD genotype was present more often in patients than in control subjects and identified a possible interaction with 1 of the chymase polymorphisms.