Angiotensin I-converting Enzyme DD Genotype Research Articles

Link between ACE I/D Gene Polymorphism and Dyslipidemia in Diabetic Nephropathy: A Case-control Study from Hyderabad, India.

Introduction:Diabetic nephropathy (DN) is the commonest single cause of end-stage renal failure, and dyslipidemia is a critical risk factor in the occurrence of DN. In the light of recent reports emphasizing the importance of angiotensin I-converting enzyme (ACE) in the modulation of plasma lipids, we sought to evaluate the influence of ACE I/D gene polymorphism with dyslipidemia status among type 2 diabetic (T2D) patients with and without nephropathy in the genetic predisposition and the progression to DN.Method:This study comprised of 600 subjects, which include patients with DN, T2D, and healthy controls (HC). Polymerase chain reaction based genotyping of ACE I/D polymorphism was performed and appropriate statistical analysis was done.Results:Out of the 600 subjects, 20 (10%) of the HC, 73 (36.5%) of the T2D group, and 125 (62.5%) of the DN subjects had dyslipidemia. The D allele (0.62) and DD (42.5) genotype frequencies were higher in the DN group in comparison with T2D and HC (P < 0.05). The genotypes also varied among patients with dyslipidemia (χ2 5.04; P < 0.05) but not in the non-dyslipidemia group. Under the co-dominant model, DD genotype conferred a risk of 1.26 (P < 0.001) toward DN, whereas the ID genotype offered protection from DN among the dyslipidemic subjects (OR = 0.05; P < 0.01). In addition, genotype-dependent difference was seen in the plasma lipid levels among study groups. A multiple logistic regression analysis revealed male gender, BMI, HbA1c, TG, HDL, and ACE DD genotype as independent risk factors for the development of DN.Conclusion:The study showed a significant predisposing association of ACE DD genotype with DN and protective effect of ID genotype on DN in the dyslipidemia subgroup.

Importance of ACE polymorphisms for endurance performance

The skeletal muscle renin-angiotensin system (RAS) plays an important role in exercise metabolism. A functional insertion (I)/deletion (D) polymorphism in the angiotensin I- converting enzyme (ACE) gene (rs4646994) has been associated with ACE activity. The ACE DD genotype is associated with increased circulating ACE levels, which are generally two times as high as those found for II genotypes. Although most reports suggest that the I allele predisposes to human endurance (1) the literature also contains some opposite data (2). These inconsistencies from genetic association studies relating to the ACE gene and its I/D polymorphism maybe attributable, partially, to epigenetic factors that have been reported to influence ACE activity. Indeed, if both copies of the ACE D/D gene are transiently methylated, ACE increased levels associated with this polymorphism, may be down-regulated. However, there have not been any reports that address whether epigenetic regulation of the ACE gene is specifically involved in modifying human endurance, but, importantly, the human ACE gene promoter has been shown to harbor CpG islands. It is well established that environmental factors may modify the epigenetic profile and that nutrition training, muscle unloading and mechanical stimulation significantly impact on performance, playing an epigenetic role . Hence, it is conceivable that some of these factors might influence the CpG islands within the ACE promoter affecting its expression. The present study is aimed at modulating the epigenetic pattern of the ACE promoter by administering arginine to professional soccer players. ACE (DD, ID, and II) will be genotyped by PCR, then the epigenetic profile of ACE (gene promoter methylation) will be determined by bisulfite method, the serum levels of angiotensin 2 will be measured by ELISA. Hence, we compare the performance capacity of soccer players exhibiting different ACE polymorphisms, by strength, speed, and endurance tests. Subsequently, we will split the subjects under study in 2 groups: group 1 will follow a mediterrean diet, group 2 will follow the same mediterrean diet supplemented with arginine. After six months we will analyze if an epigenetic regulation of the ACE gene has occurred, modulating endurance performance.

Angiotensin I-converting enzyme gene polymorphism enhances the effect of hypercholesterolemia on the risk of coronary heart disease in a general Japanese population: the hisayama study.

The angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism has been reported to be implicated in susceptibility to coronary heart disease (CHD). However, this association remains inconclusive. The purpose of this study was to clarify the association between the I/D polymorphism of the ACE gene and the development of CHD in a Japanese general population and investigate whether the effects of traditional risk factors on the risk of CHD are heterogeneous among ACE genotypes. The subjects included 2,125 community-dwelling individuals 40 years of age or older without cardiovascular disease for whom genetic information was available. All patients were prospectively followed for 19 years, and the association between the ACE polymorphism and the incidence of CHD was examined based on the interactions with traditional risk factors, such as hypercholesterolemia, hypertension, diabetes and smoking. A total of 161 CHD events occurred during the follow-up period. The age- and sex-adjusted incidence of CHD was not significantly different among the genotypes (5.8, 5.2, and 6.9 per 1,000person-years for genotypes II, ID and DD, respectively). In a stratified analysis, however, the ACE DD genotype was found to significantly accelerate the risk of developing CHD by hypercholesterolemia (hazard ratio [HR]=4.50, 95% confidence interval=2.02-10.04 for hypercholesterolemia with the DD genotype; HR=1.48, 95% CI=1.04-2.12 for hypercholesterolemia with the ID＋II genotype; P for interaction=0.01), even after adjusting for other confounding factors, whereas no such associations were observed for hypertension, diabetes or smoking. The current findings suggest that the ACE DD genotype enhances the effect of hypercholesterolemia on the development of CHD in the general Japanese population.

Association of Angiotensin-I-Converting Enzyme (ACE) Insertion/Deletion Gene Polymorphism with End Stage Renal Disease in Egyptian Patients

Angiotensin-I-converting enzyme (ACE) insertion/deletion (I/D) polymorphism has been associated with the genetic susceptibility to end stage renal disease (ESRD) in different populations. ACE DD genotype and D allele are associated with ESRD as risk factors in several studies. In this study, we investigated the association between ACE I/D gene polymorphism and ESRD in the Egyptian patients. Frequencies of D allele and DD genotype were significantly increased, while frequencies of I allele and ID genotype were significantly decreased in the ESRD patients when compared with the control subjects (P = .012, OR = 1.82, 95% CI = 1.139-2.915 for DD) and (P = .018, OR = 1.6, 95% CI = 1.082-2.33 for D). In conclusion, ACE DD genotype and D allele are associated with ESRD as risk factors for ESRD in the Egyptian population.

The Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and the Risk for Restenosis After PTCA.

The therapeutic benefit of percutaneous transluminal coronary angioplasty (PTCA) is limited by restenosis in about 30% of patients. The underlying mechanisms are currently not well understood. Besides clinical and angiographic variables, genetic factors may be involved. We determined the angiotensin I-converting enzyme (ACE) I/D genotype as a possible risk factor for restenosis in 511 consecutive patients who had undergone successful PTCA and follow-up angiography. Clinical and angiographic variables were also considered as possible predictors of restenosis. One hundred sixty patients had restenosis as defined by a greater than 50% progression of residual stenosis of the dilated segment at follow-up angiography. There were significantly more patients with the ACE DD genotype in the restenosis than in the no-restenosis group. This difference did not remain statistically significant in an analysis of covariance that included genetic and clinical variables. Patients who subsequently developed restenosis had a higher degree of stenosis and more severe lesions before PTCA as well as less residual stenosis immediately after PTCA. We conclude that the ACE DD genotype is not an independent risk factor for restenosis after PTCA.

The ACE deletion allele is associated with Israeli elite endurance athletes

An Alu insertion (I)/deletion (D) polymorphism in the angiotensin I converting enzyme (ACE) gene has been associated with ACE activity. Opposing effects on elite athletic performance have been proposed for the I and D alleles; while the D allele favours improved endurance ability, the I allele promotes more power‐orientated events. We tested this hypothesis by determining the frequency of ACE ID alleles amongst 121 Israeli top‐level athletes classified by their sporting discipline (marathon runners or sprinters). Genotyping for ACE ID was performed using polymerase chain reaction on DNA from leucocytes. The ACE genotype and allele frequencies were compared with those of 247 healthy individuals. Allele and genotype frequencies differed significantly between the groups. The frequency of the D allele was 0.77 in the marathon runners, 0.66 in the control subjects (P= 0.01) and 0.57 in the sprinters (P= 0.002). The ACE DD genotype was more prevalent among the endurance athletes (0.62) than among the control subjects (0.43, P= 0.004) and the power athletes (0.34, P= 0.004). In the group of elite athletes, the odds ratio of ACE DD genotype being an endurance athlete was 3.26 (95% confidence interval 1.49–7.11), and of ACE II genotype was 0.41 (95% confidence interval 0.14–1.19). We conclude that in Israeli elite marathon runners the frequency of the ACE D allele and ACE DD genotype seems to be higher than in sprinters, suggesting a positive association between the D allele and the likelihood of being an elite endurance athlete in some ethnic groups.

Polymorphisms of ACE2 Gene are Associated With Essential Hypertension and Antihypertensive Effects of Captopril in Women

ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the reninangiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two casecontrol studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6-fold risk for hypertension in women (95% confidence interval (CI), 1.132.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34-fold (95% CI, 1.754.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.

Reduced plasma levels of angiotensin-(1-7) and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

The relationship between preeclampsia and the renin-angiotensin system (RAS) is poorly understood. Angiotensin I-converting enzyme (ACE) is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II) and inactivating the vasodilator angiotensin-(1-7) (Ang-(1-7)). ACE (I/D) polymorphism is characterized by the insertion (I) or deletion (D) of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D) polymorphism was correlated with plasma Ang-(1-7) levels and several RAS components in both preeclamptic (N = 20) and normotensive pregnant women (N = 20). The percentage of the ACE DD genotype (60%) in the preeclamptic group was higher than that for the control group (35%); however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260). The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 +/- 5.06 vs 27.6 +/- 3.25 nmol Hip-His Leu(-1) min(-1) mL(-1) in DD control patients; P = 0.0005). Plasma renin activity was markedly reduced in preeclampsia (0.81 +/- 0.2 vs 3.43 +/- 0.8 ng Ang I mL plasma(-1) h(-1) in DD normotensive patients; P = 0.0012). A reduced plasma level of Ang-(1-7) was also observed in preeclamptic women (15.6 +/- 1.3 vs 22.7 +/- 2.5 pg/mL in the DD control group; P = 0.0146). In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

Polymorphism of renin‐angiotensin system genes in IgA nephropathy

Individuals are prone to disease because of certain disease-susceptible genes. The angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D), the angiotensinogen (AGT) gene, M235T, and the angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with IgA nephropathy (IgAN) and its progression. Several studies on Caucasians and Japanese patients have reported contradictory results. We determined these polymorphisms in 118 Chinese patients with IgAN and 94 healthy Chinese subjects to assess their clinical impact. Genotyping was performed with DNA isolated from peripheral leucocytes, polymerase chain reaction amplification of the polymorphic sequence, restriction enzymes digestion, and separation and identification of DNA fragments. Clinical data at renal biopsy and final status on renal function were determined from patients' records. Comparing all IgAN patients with controls, AGT and ATR genotype distributions were similar, whereas there was a significant increase in the ACE DD genotype (P < 0.05). When comparing patients with end-stage renal failure (IgAN-ESRF) and those without (IgAN-nonESRF), there was no difference among the three gene polymorphisms. In contrast, there were significant differences in higher male prevalence (P < 0.05), increased serum creatinine at presentation (P < 0.05), more sclerosis (P < 0.01) and higher tubulointerstitial lesion score (P < 0.001) in the IgAN-ESRF group. Among the ACE, AGT and ATR gene polymorphisms, only the DD genotype may predispose the individual to IgAN in the Chinese population. None are significant for prognosticating ESRF.

Renin–angiotensin system and haemostasis gene polymorphisms and outcome after coronary artery bypass graft surgery

Background Coronary artery bypass graft surgery is associated with a considerable 2-year mortality rate. Gene polymorphisms of the renin–angiotensin system may be associated with the risk of hypertension and cardiovascular disease. The angiotensin I-converting enzyme DD genotype has recently been identified as independent predictor of the outcome after coronary artery bypass graft surgery. Genetic factors of the clotting system may be related to the risk of myocardial infarction and restenosis after coronary interventions. The aims of the present study were to investigate whether gene polymorphisms of the renin–angiotensin system (angiotensinogen 235 M/T, angiotensin II type 1 receptor 1166 A/C) or the clotting system (glycoprotein IIIa PlA1/PlA2 and factor V Leiden 1691 G/A) are associated with the outcome after coronary artery bypass grafting. Methods A study population of 247 patients was followed-up 2 years after coronary artery bypass graft surgery. The primary end-point was total mortality. The secondary end-point was mortality from cardiac cause or the need for myocardial revascularization (percutaneous coronary interventions or recurrent surgery) during follow-up. Geno typing was performed by polymerase chain reaction- and restriction fragment length polymorphism-based techniques. Results An older age and the non-use of the internal mammary artery graft were identified as independent predictors of the primary end-point after coronary artery bypass grafting. A decreased left ventricular ejection fraction was an independent predictor for the secondary end-point. No association was found between any of the genetic factors and the outcomes after coronary artery bypass graft surgery in the main factor regression models. However, the angiotensin II type 1 receptor 1166 A/C gene polymorphism modulated the effects of age on the primary end-point, and the angiotensinogen 235 M/T gene polymorphism modulated the effects of age on the secondary end-point. Conclusion We conclude that there are interactions between the angiotensin II type 1 receptor 1166 A/C as well as the angiotensinogen 235 M/T gene polymorphism and age with respect to the outcome after coronary artery bypass graft surgery. The glycoprotein IIIa PlA1/PlA2 and the factor V Leiden 1691 G/A gene polymorphisms were not associated with mid-term mortality or cardiac morbidity after coronary artery bypass grafting.

ACE genotype and cognitive decline in an African-Caribbean population

The insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene is believed to influence risk of cerebrovascular disease. However, associations with cognitive outcomes remain controversial. As far as we are aware, all studies to date have been carried out in white American or European populations. African-Caribbean populations have high prevalence rates of hypertension, diabetes and cerebrovascular disease but risk factors for cognitive outcomes remain under-researched. In a UK community sample of 148 African-Caribbean people aged 55–75 years, we investigated the association between ACE genotype and cognitive decline over 3 years using a battery of repeated tests. No direct association was found between ACE genotype and decline. However, the association between increased age and cognitive decline was significantly stronger in people with the ACE DD genotype (odds ratio 3.6 per 5-year increase, 95% CI: 1.9–6.7) compared to those with ID/II genotype (odds ratio 0.7, 95% CI 0.4–1.2). This interaction was particularly strong for decline in verbal memory and was not apparently mediated by vascular risk factors measured at baseline.

Angiotensin I-Converting Enzyme Insertion/Deletion Polymorphism and Cardiac Mortality and Morbidity After Coronary Artery Bypass Graft Surgery

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). 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. The ACE DD genotype is associated with increased midterm mortality and cardiac morbidity after CABG.

Renin-angiotensin-aldosterone system (RAAS) gene polymorphism as a risk factor of coronary in-stent restenosis.

Intimal proliferation is a main cause of in-stent restenosis. Over-excretion of angiotensin I converting enzyme (ACE) and aldosterone is reported to stimulate intimal hyperplasia and the genetic effect of these molecules may alter the process of in-stent restenosis. We hypothesized that the genetic polymorphisms that alter the expression of genes such as ACE I/D, CYP11B2-344C/T, and AGT M235T can affect in-stent restenosis. We analyzed the angiographic and clinical data of 238 patients (272 stents) who underwent coronary stenting and follow-up angiography, and analyzed the genotypes of ACE I/D, CYP11B2-344T/C, and AGT M235T. There was no significant difference in age, sex, or lipid profiles between the patent and restenosis groups. Diabetes mellitus was more frequent in the binary restenosis group. Quantitative computer-assisted angiographic (QCA) analysis revealed that the risk of in-stent restenosis increased with lesion length and was inversely proportional to post- stenting minimal luminal diameter (MLD) and reference diameter. There was no difference in the frequency of binary restenosis between genotypes in each of the three genes. However, follow-up MLD was significantly smaller in the ACE DD genotype than in the ACE II or ID genotypes. Defining restenosis as MLD < 2 mm, the restenosis rate was significantly higher in the ACE DD genotype than in the ACE II or ID genotypes. There was no significant synergistic effect between the three gene polymorphisms. In conclusion, while the ACE I/D polymorphism promoted the progress of in-stent restenosis and was of clinical significance, the other potential variables examined did not correlate with in-stent restenosis.

Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene is not associated with restenosis after coronary stent placement.

The renin-angiotensin system is thought to play a role in coronary thrombosis and restenosis. Plasma angiotensin I-converting enzyme (ACE) activity is associated with an insertion/deletion polymorphism in the gene coding for ACE. The objective of this study was to test the hypothesis that the D allele of the ACE gene is associated with a higher risk for restenosis after coronary stent placement. This prospective study included 1850 consecutive patients with coronary artery disease who underwent intracoronary stent implantation. The adverse clinical events recorded were death, myocardial infarction, and target vessel revascularization. The primary end point of the study was restenosis (>/=50% diameter stenosis at follow-up angiography performed in 84% of the patients). The secondary end point was clinical outcome 1 year after the procedure. The restenosis rate at the 6-month angiographic follow-up was 32.8% in patients with the II genotype, 34.0% for patients with the ID genotype, and 31.2% for patients with the DD genotype (P=0.62). One-year event-free survival was 77.7% in patients with genotype II, 75.2% in patients with genotype ID, and 75.5% in patients with genotype DD (P=0.54). The lack of association was also present in the subgroup of patients with a low risk for restenosis: the restenosis rate was 21.7% in II carriers, 23.4% in ID carriers, and 19.7% in DD carriers (P=0.83). The ACE DD genotype or D allele does not influence the 1-year clinical and angiographic outcome of patients undergoing coronary stent placement. These data suggest that routine determination of the ACE genotype may not help identify patients who are at a higher risk of thrombotic and restenotic events after coronary stent placement.

The angiotensinogen gene 235T variant is associated with an increased risk of restenosis after percutaneous transluminal coronary angioplasty

The therapeutic benefit of percutaneous transluminal coronary angioplasty (PTCA) is limited by restenosis in 30-40% of patients. The underlying mechanisms are currently not well understood. Besides clinical and angiographic variables, genetic factors may be involved. In the present study, we investigated the associations between the angiotensinogen T174M and M235T, the angiotensin I-converting enzyme (ACE) I/D and the angiotensin II type 1 receptor A1166C gene polymorphisms and restenosis in 511 patients who had undergone successful PTCA (without stenting) and follow-up angiography. Clinical and angiographic variables were also considered as possible predictors of restenosis. Stenosis severity was estimated by visual inspection of the angiograms. Altogether, 160 patients had restenosis, as defined by a greater than 50% reduction in the diameter of the dilated segment at follow-up angiography compared with the findings immediately following angioplasty. There were significantly more carriers of the angiotensinogen 235T allele and more patients with the ACE DD genotype in the restenosis group than in the no restenosis group, but only the angiotensinogen 235T allele (and not the ACE DD genotype) remained significantly associated with restenosis following multifactorial analyses. No differences between the two groups were found with respect to the other gene polymorphisms. Patients who subsequently developed restenosis had a higher degree of stenosis and more severe lesions before PTCA, as well as less residual stenosis immediately after PTCA. We conclude that the angiotensinogen M235T gene polymorphism may be an independent predictor of restenosis after PTCA.

Genetic polymorphism of renin-angiotensin system is not associated with diabetic vascular complications in Japanese subjects with long-term insulin dependent diabetes mellitus

In a hospital cohort study, we examined whether or not ACE (Angiotensin-I converting enzyme) and AGT (Angiotensinogen) gene polymorphisms were associated with the development of nephropathy in long-term Japanese insulin-dependent diabetes mellitus (IDDM) patients with or without proliferative retinopathy, and whether or not the polymorphisms were associated with an arteriosclerotic family history in first degree relatives of the patients. A total of 201 patients with IDDM for more than 10 years and 159 patients with IDDM for more than 15 years were randomly selected in our hospital. All patients received uniform diabetes management and were divided into three groups, no nephropathy, incipient nephropathy and clinical nephropathy groups. There were no differences in clinical characteristics excluding urinary albumin to creatinine ratio and systolic blood pressure between the three groups. ACE I/D polymorphism was related to plasma ACE activity, but there were no associations between ACE I/D polymorphism and the development of diabetic nephropathy, nor was renal deterioration observed in patients with proliferative retinopathy even in those with a history of diabetes for more than 15 years. The AGT polymorphism did not have an additive effect on the association between ACE polymorphism and the development of diabetic nephropathy in patients with or without retinopathy. Development of diabetic nephropathy in the patients with or without proliferative retinopathy did not result in ACE or AGT polymorphisms. On the other hand, the ACE DD genotype was associated with a family history of ischemic heart disease in first degree relatives ( χ 2 score=9.04, P<0.05). ACE and AGT gene polymorphisms may not play a role in the protective or accelerative effect against the development of diabetic nephropathy in the patients with or without proliferative retinopathy, but ACE gene polymorphism might be related to an arteriosclerotic family history in Japanese IDDM 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.

The deletion allele of the angiotensin I converting enzyme gene as a genetic susceptibility factor for cognitive impairment

Experimental evidences suggest an implication of the renin angiotensin system (RAS) as a potential determinant of cognitive functions. To explore this hypothesis, we compared the distribution of an insertion (1)/deletion (D) polymorphism of the gene coding for the angiotensin I converting enzyme ( ACE), a key enzyme of the RAS, in 228 elderly with cognitive impairment to that of 255 controls. The ACE D allele frequency was higher in the group with cognitive impairment (0.594) than in controls (0.514) ( P < 0.02). The ACE DD genotype carriers had an increased risk of cognitive impairment ( OR = 1.60, 95% CI (1.04−2.36), P < 0.03), independent of other risk factors of cognitive impairment: age, gender and presence of the apolipoprotein E ϵ4 allele. This association was stronger in men ( OR = 3.25, 95% CI (1.40−7.58), P < 0.006). This result suggests a possible implication of the RAS in human brain and cognitive functions.

Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease

The D allele of an insertion/deletion ( I D ) polymorphism in the angiotensin I-converting enzyme (ACE) gene is associated with a risk of myocardial infarction, and the relative risk associated with the ACE D allele is increased by the C allele of an angiotensin II type 1 receptor (AT 1R) gene polymorphism (an A → C transversion at nucleotide position 1166) [28]. The relation of the ACE and AT 1R gene polymorphisms to coronary heart disease and the severity of coronary artery stenosis has now been investigated in 133 patients with myocardial infarction (MI) or angina pectoris who underwent coronary angiography and in 258 control subjects. The frequency of the ACE DD genotype as compared with non- DD was significantly higher in the patients who experienced an MI and in the low-risk patients than that in the controls ( P < 0.05). The DD genotype showed a significantly increased risk of MI (odds ratio 1.85). The frequency of the AT 1R A C genotypes did not differ between the patients and the controls. The severity of coronary stenosis in the patients was estimated by the number of affected vessels (> 75% stenosis) and the coronary score of Gensini. Neither the number of affected vessels nor the coronary score differed among the ACE I D genotypes. However, the number of affected vessels was significantly greater in patients with the AT 1R AC genotype than in those with the AA genotype (1.93 ± 0.27 vs. 1.27 ± 0.99; P < 0.05) ( CC genotype was not found in the patients). After excluding patients with diabetes mellitus, the coronary score of those with the AC genotype was also significantly higher than in those with the AA genotype (51.7 ± 34.4 vs. 18.2 ± 23.3; P < 0.01). These results suggest that the ACE D allele is associated with the occurrence of myocardial infarction, while the AT 1R C allele is involved in the development of the coronary artery stenosis.

HYPOTHESIS: AN ANGIOTENSIN CONVERTING ENZYME/GENOTYPE, PRESENT IN ONE IN THREE CAUCASIANS, IS ASSOCIATED WITH AN INCREASED MORTALITY RATE

1. This review argues that the deletion (D) allele of an insertion (I)/deletion polymorphism of the angiotensin I-converting enzyme (ACE) gene is a marker for a variant associated with increased ACE expression, as well as myocardial infarction (MI) and other life-threatening conditions. 2. By examination of I/D frequency in different age groups of individuals having well-known risk factors, it appears that homozygosity for the D allele may be associated with an increased risk of premature death in subjects at high-risk of cardiovascular events. For the risk factor hypertension, the odds ratio for DD vs II in patients aged > or = 60 years was 6.6. 3. Besides in MI itself, the DD genotype appears to be also more prevalent in MI patients who develop restenosis several months after balloon angioplasty, patients with various forms of heart failure, those with ventricular hypertrophy and diabetic patients who develop nephropathy. 4. Particular genotypes of other components of the renin-angiotensin system may add to the risk conferred by the ACE DD genotype. 5. Emerging evidence therefore suggests that the ACE genotype may eventually be placed on the list of common, well-known risk factors for fatal cardiovascular events.