Angiotensin-converting enzyme gene I/D polymorphism in malignant hypertension

BACKGROUND: The mechanism of the rapid transition of a stable benign hypertensive disease to a severe and devastating malignant hypertension is not fully understood. However, the renin angiotensin system, which is highly activated in malignant hypertension, is established as an important pathogenetic factor in different cardiovascular and renal diseases. Over the last decade, a polymorphism in genes regulating this system has been found. This includes the 287 bp sequence deletion (D)/insertion (I) polymorphism in the angiotensin-converting enzyme (ACE) gene and the methionine (M) to threonine (T) point mutation polymorphism in the angiotensinogen (AGT) gene. These gene polymorphisms have been associated with various cardiovascular and renal diseases and the aim of this study was to investigate whether they were linked to malignant hypertension. METHODS: Forty-two patients with malignant hypertension (mean age 55 years), 42 patients with non-malignant hypertension (mean age 57 years) and 85 normotensive control subjects (mean age 42 years) were investigated with respect to ACE I/D and AGT M/T genotypes. DNA was prepared by standard methods from isolated white blood cells and analysed by the PCR technique. The PCR reaction used in the detection of the ACE I/D polymorphism was optimized for an equal amplification of the I and D alleles. RESULTS: The frequency of the DD genotype was significantly increased in patients with malignant hypertension (43%) compared with patients with non-malignant hypertension (14%) and normotensive control subjects (18%) (p <0.01) for both. The frequency distribution of AGT M/T genotype did not differ between patients with malignant and non-malignant hypertension. CONCLUSION: The DD genotype of the ACE gene occurred more than twice as often in malignant hypertension than in non-malignant hypertension and indicates that ACE gene polymorphism is a significant risk factor for initiation of malignant hypertension.     

Genetic factors in hypertension. Angiotensin-converting enzyme polymorphism

AIM: The key enzyme of the renin-angiotensin-aldosterone system angiotensin-converting enzyme (ACE), shows the genetic polymorphism responsible for the varying activity of this enzyme. In a study of randomly chosen families we analyzed the relationship between insertion/deletion (I/D) polymorphism of the ACE and ambulatory blood pressure (ABP), left ventricular mass index (LVMI) and carotid intima-media thickness (IMT). METHODS: The study population consisted of 127 parents and 167 offspring. All subjects underwent 24 hr ABP monitoring using a SpaceLabs 90207 device. 2D and M-mode echocardiograms were also obtained. The carotid intima-media thickness (IMT) was assessed by ultrasound. The I/D polymorphism of the ACE gene was measured with the use of PCR method. For statistical analysis, co-variables and correlations between relatives were taken into account. RESULTS: The frequency of genotypes was: 27.2% for DD homozygotes, 49.7% for DI heterozygotes and 23.1% for II homozygotes, being in Hardy-Weinberg equilibrium (P=0.97). There was no relationship between the ACE gene polymorphism and ABP, LVMI or carotid IMT in parents nor their offspring. The transmission disequilibrium tests for quantitative traits showed only a slight tendency towards the influence of the polymorphism on LVMI (P=0.06). CONCLUSIONS: In the study group of nuclear families, I/D polymorphism of the ACE gene did not influence blood pressure, left ventricular mass or carotid intima-media thickness.     

Angiotensin-converting enzyme gene polymorphism in patients with psoriatic arthritis

To investigate the frequency of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism genotypes in adults with psoriatic arthritis (PsA), 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 mechanism. The frequency of ACE gene I/D polymorphism genotypes was determined in 51 adults with PsA from Kuwait, and compared to that in 100 ethnically matched healthy controls using polymerase chain reaction. The distribution of ACE I/D polymorphism and allele frequencies in PsA patients were not significantly different from controls (P > 0.05). Further analyses of PsA patients showed that ACE I/D gene polymorphism was not associated with family history, clinical manifestations, and disease severity. However, the frequency of II genotype was significantly higher in patients with late disease onset than in those with early onset (25 vs. 3%; P = 0.04). No difference was found between the distribution of the ACE genotype in PsA patients and the general population in Kuwait. However, the presence of II genotype may confer susceptibility to the development of late onset PsA.     

Angiotensin-converting enzyme I/D polymorphism and hypertension: the Ohasama study

OBJECTIVE : Angiotensin-converting enzyme (ACE) I/D polymorphism in intron 16 of the ACE gene was analyzed in a general Japanese population in relation to self-blood pressure (BP) measurement at home (home BP) and ambulatory BP monitoring (ABPM) to determine the association between genetic variants of this polymorphism and hypertension. DESIGN : A cross-sectional study. METHODS AND RESULTS : We genotyped the ACE I/D polymorphism in 1245 subjects with home BP and 803 subjects with ABPM in Ohasama, a rural community in Japan. All the subjects were 40 years of age and over, and gave written informed consent for the present genetic analysis. Hypertensive subjects were defined as those receiving antihypertensive drugs and those who had a home BP higher than 135 mmHg in systole and/or higher than 85 mmHg in diastole. The frequencies of the II, ID, and DD genotypes in these Japanese subjects were 0.45, 0.45, and 0.10, indicating a lower frequency of the D allele (0.33) than in Caucasians. There was no significant difference of BP level, prevalence of hypertension or nocturnal decline in BP among the genotypes. There were no differences in the prevalence of previous cardiovascular disease, age, body mass index, male gender, smoking, or biochemical and hormonal parameters among the three genotypes. CONCLUSION : The present results indicate the absence of direct effects of the ACE D-allele on BP level, prevalence of hypertension, prevalence of cardiovascular disease, and circadian BP variation. We conclude there is little association between ACE I/D polymorphism and hypertension in the general Japanese population.     

Angiotensin-converting enzyme gene polymorphism in patients with obstructive sleep apnea

Obstructive sleep apnea (OSA) is often accompanied by cardiovascular and metabolic disorders. The renin-angiotensin system plays an important role of the cardiovascular regulation. The activity of the angiotensin converting enzyme is genetically determined. The aim of the study was to estimate the relation between angiotensin converting gene polymorphism and cardiovascular diseases or familial history in patients with obstructive sleep apnea. 63 patients with OSA were enrolled to the study. Arterial hypertension was diagnosed in 30 cases, ischaemic heart disease in 5 cases and 10 patients suffered from both mentioned diseases. RESULT: The observed ACE genotype frequencies in the study group were II: ID: DD: 23.81: 47.62: 28.57%, in the hypertension subgroup II: ID: DD--30.0: 46.6: 23.3%. No differences in the study group were observed in relation to familial history :DI:II--30.43: 43.48: 26.09% vs 25.64: 48.72: 25.4%. CONCLUSIONS: 1. In the study group there was no association between ACE polymorphism and OSA. 2. There were also no association between the polymorphism of ACE and cardiac diseases or familial history of cardiac diseases in OSA group. 3. The polymorphism of ACE is not a risk factor for OSA.     

Angiotensin-converting enzyme gene I/D polymorphism and carotid artery disease in renovascular hypertension

There is evidence linking the activation of the renin-angiotensin system (RAS) with target organ damage in renovascular hypertension (RVH). A genetic association of the DD genotype of the angiotensin-converting enzyme (ACE) gene with cardiovascular complications has been found in various clinical conditions. The aim of our study was to determine whether the insertion/deletion (I/D) polymorphism of the ACE gene is associated with the high prevalence of target organ damage reported in RVH. A total of 65 atherosclerotic patients (age 68.2 +/- 5.2 years) with RVH and 49 atherosclerotic patients (age 68.0 +/- 6.3 years) with essential hypertension (EH) were sequentially enrolled when attending the outpatient clinic for specialist assessment of their vascular disorder. Cardiac, renal, and vascular involvement were assessed in both groups and blood was taken for genetic analysis. Patients with RVH had a higher prevalence of left ventricular hypertrophy (LVH), carotid artery disease, and albuminuria than those with EH. In RVH, but not in EH, the DD genotype was significantly associated with severe arterial disease. In RVH, carotid disease (lumen narrowing >60%) was present in 62% of DD patients versus 25% of the other genotypes (OR = 4.90, 95% CI: 1.70-14.13). Such an association was also present in peripheral vascular disease: 72.4% in DD patients versus 41.6% in the other genotypes (OR = 3.67, 95% CI = 1.29-10.36). Logistic regression analysis showed that the DD genotype was the strongest predictor of risk of severe carotid disease. We conclude that, in atherosclerotic RVH, there is an association of the severity of vascular disease with the DD genotype of the ACE gene.     

Angiotensin-converting enzyme D/I gene polymorphism and age-related changes in pulse pressure in subjects with hypertension

Background- Few studies have examined the possible influence of gene polymorphisms on the increase of systolic blood pressure (SBP) and pulse pressure (PP) with age, although in older populations, SBP>160 mm Hg or PP>60 mm Hg are strong mechanical factors predicting cardiovascular mortality. METHODS AND RESULTS: This cross-sectional study involved 315 men and 154 women with either systolic-diastolic or isolated systolic hypertension. Using polymerase chain reaction, the angiotensin-converting enzyme (ACE) D/I gene polymorphism was investigated separately in men and women, enabling us to determine the relationships between age and PP, SBP, and diastolic blood pressure (DBP) for each genotype in each population. In men, most of which were under 50 years of age, the slope of the age-PP and age-SBP (but not age-DBP) relationships differed significantly between genotypes (P=0.0096 and 0.0175). The interslope difference was unmodified after adjustments involving all of the following factors together: plasma glucose, cholesterol, creatinine, potassium, body weight, tobacco consumption, mean blood pressure, and previous antihypertensive therapy. Adjustment of the two latter parameters alone significantly attenuated the interslope difference. Based on logistic regressions, the DD genotype was shown to independently predict a PP>60 mm Hg but not a SBP>160 mm Hg. CONCLUSIONS: In men, the ACE D/I gene polymorphism independently modulates age-related increase of PP, and potentially modulates the resulting cardiovascular risk. This finding requires the development of long-term follow-up.     

Angiotensin-converting enzyme gene polymorphism in Kuwaiti patients with systemic lupus erythematosus

OBJECTIVE: To investigate the frequency of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism genotypes in patients with systemic lupus erythematosus (SLE), and to study the correlation between I/D polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement, lupus nephritis and disease severity. METHODS: The frequency of ACE gene I/D polymorphism genotypes was determined in 92 patients with SLE from Kuwait, and compared to that in 100 ethnically matched healthy controls using the polymerase chain reaction. RESULTS: The distribution of ACE I/D polymorphism and allele frequencies in SLE patients was not significantly different from controls. Further analyses of SLE patients showed that there was a significant association between DD genotype and Raynaud's phenomenon (p=0.008, odd ratio=5.4, 95% confidence interval: 1.6-18.6). However, there was no significant association between the ACE genotype and lupus nephritis or disease severity. CONCLUSION: No difference was found between the distribution of the ACE genotype in SLE patients and the general pop-ulation in Kuwait. However, the presence of the DD genotype may confer susceptibility to the development of vascular morbidity.     

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.     

Angiotensin-converting enzyme gene polymorphism in patients with primary disturbances of cardiac conduction

Increased frequencies of angiotensin-converting enzyme (ACE) D-allele and ID-genotype among patients with idiopathic atrioventricular blocks and I allele and II genotype among patients with idiopathic intraventricular blocks allow to consider these genotypes risk factors of corresponding disturbances of cardiac conduction. Decreased frequency of ACE I allele and II genotype among patients with idiopathic atrioventricular blocks is indicative of a possible protective role of II genotype against development of this type of cardiac conduction defect. Low frequency of D allele and genotype D prevents derangements of conduction in His-Purkinje system.     

Angiotensin-converting enzyme gene polymorphism and its association with essential hypertension in a Tibetan population.

There is strong evidence to support the idea that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of essential hypertension (EH) and its complications. However, existing data about the association of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with blood pressure is conflicting, mainly due to racial differences and environmental exposure status. We therefore conducted a case control study to observe the relationship between ACE I/D polymorphism and EH in a Tibetan population who live in relatively isolated areas and are genetically homogeneous. The study was conducted at stable residential communities in the urban district of Lhasa, the capital of the Tibet autonomous region, China, and 106 unrelated EH patients and 135 normotensIve subjects were recruited. PCR, PCR/RFLP and PCR-SSCP were carried out to study the association between RAS genes and EH. Frequencies for the DD, ID and II genotypes were 27, 47 and 29 in hypertensive subjects, and 15, 60 and 48 in normotensive subjects, respectively. Derived allele frequencies for the I and D alleles were 0.51 and 0.49 in hypertensive subjects and 0.64 and 0.36 in normotensive subjects. There were significant differences in genotype distribution and derived allele frequency between these two groups. The genotype and allele frequencies of the ACE gene differed significantly between hypertensive and normotensive females (p>0.05), but there were no differences in males. In females, the DBP and MAP level were significantly higher for the DD than for the ID and II genotype, and SBP was significantly higher for the DD than for the II genotype. But in males, there were no significant differences in blood pressure among ACE genotypes. The results showed a significant association between the D allele of the ACE gene and hypertension in Tibetan women but not in Tibetan men.     

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in African-American patients with hypertension

African-American patients with hypertension are less responsive to blockers of the renin-angiotensin system than white patients. The relative efficacy of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and the extent of cross-resistance to these agents has not been studied. Fifty-one African-American patients with stage 1-2 hypertension were randomly assigned to enalapril or candesartan cilexetil for 8 weeks and then crossed over to the other treatment. Nonresponders to enalapril and candesartan used a combination of the two. Of the 51 patients randomized (average age 61.2+/-9 years, blood pressure 148/100 mm Hg, heart rate 74 bpm, and body weight 92.8 kg), 44 completed the study. At Week 8, systolic blood pressure (SBP) was reduced by 4.8 mm Hg with enalapril and by 4.7 mm Hg with candesartan (p=NS), and diastolic blood pressure (DBP) was reduced by 4.4 mm Hg and 5.6 mm Hg, respectively (p<0.04). Of these 44 patients, 11 (25%) responded to enalapril by SBP criteria and 19 (43%) by DBP criteria. Seven patients (16%) responded by both SBP and DBP criteria, and 21 patients (48%) were nonresponders. With candesartan, 13 patients (29%) responded by SBP criteria, 20 (45%) by DBP criteria and 12 (27%) by both SBP and DBP criteria (p<0.04, compared with enalapril). Only six patients (14%) responded to both enalapril and candesartan by both SBP and DBP criteria. Of the 18 nonresponders to either enalapril or candesartan, the combination of the two had minimal additional effect. Significant changes in plasma-renin activity and angiotensin II levels were noted only with the high dose of each drug. In this small group of patients, treatment with candesartan resulted in slightly higher response and control rates than enalapril, more than 40% of patients who responded to enalapril did not respond to candesartan and vice versa, and in nonresponders, a combination of candesartan and enalapril offered little additional antihypertensive effect.     

血管紧张素转换酶基因多态性与卒中

血管紧张素转换酶(angiotensin converting enzyme,ACE)基因是卒中遗传易感性研究的主要候选基因之一,但ACE基因多态性与卒中的相关性还存在着争议.文章就近年来有关ACE基因多态性与卒中相关性的研究进展进行了综述.     

Angiotensin-converting enzyme gene polymorphism in a cohort of coronary angiography patients

An association between a polymorphism of the angiotensin-converting enzyme (ACE) gene and myocardial infarction (MI) in men has been previously reported. The present study examines the association between ACE genotype, atherosclerosis, MI, hypertension and other cardiovascular risk factors in Caucasian men (n=576) and women (n=124) who have undergone coronary angiography. Gene frequencies are also reported for African-American men (n=56). Genotype determination was based on the presence (allele I) or absence (allele D) of a 287 nucleotide Alu sequence in intron 16 of the ACE gene. Genotype frequencies for DD, ID and II were: 30.9, 47.7, 21.4% for Caucasian men; 28.2, 48.4, 23.4% for Caucasian women; and 30.4, 46.4, 23.2% for African-American men. There were no statistically significant associations between ACE genotype and number of plaques (> or =10% obstruction), lipid variables, or body mass index (BMI) for Caucasian men. Caucasian women with the DD genotype had on average fewer plaques, but this was accounted for by their younger ages. In Caucasian males, the DD genotype independently contributed to the presence of hypertension (odds ratio=1.8, 95% CI 1.1-2.9) after adjusting for age and BMI. In Caucasian males with total cholesterol levels less than 200 mg/dl (n=237), the DD (odds ratio=2.5, 95% CI 1.2-5.4) and ID genotypes (odds ratio=2.2, 95% CI 1.1-4.4) were associated with a history of MI.     

Angiotensin-converting enzyme insertion/deletion gene polymorphism in inflammatory bowel diseases

INTRODUCTION: The renin-angiotensin system is strictly related to the kallikrein-kinin system and both are involved in many physiological and disease conditions and possibly in the pathogenesis of inflammatory bowel disease (IBD). Angiotensin-converting enzyme (ACE) is the pivotal enzyme of the renin-angiotensin system and the main catabolic enzyme of the kallikrein-kinin system. The ACE I/D (insertion/deletion) is a polymorphism of the gene encoding for ACE: participants who are homozygous for the D allele exhibit higher ACE levels, which in turn appear to play a deleterious role in several diseases. AIM: To study the prevalence of ACE I/D polymorphism in IBD patients and its possible association with disease features. METHODS: A total of 232 IBD patients, 124 with ulcerative colitis (UC) and 108 with Crohn's disease and 99 healthy controls were genotyped for the ACE I/D polymorphism. RESULTS: DD, ID and II genotypes distribution did not show significant differences between IBD patients and controls: 42.2 vs. 40.4%, 42.7 vs. 47.5% and 15.1 vs. 12.1%, respectively. No significant difference was observed between Crohn's disease and UC patients. Within UC patients, the presence of DD genotype and the carriage of the D allele were significantly associated with the presence of extraintestinal manifestations: odds ratio (OR) 4.08, 95% confidence interval (CI): 1.62-10.28; P<0.003 and OR=3.07, 95% CI: 1.45-6.48; P<0.003, respectively. No significant association was found with other IBD clinical features. CONCLUSIONS: The ACE I/D polymorphism is not associated with IBDs but the D allele appears to increase the risk of developing extraintestinal manifestations in UC patients.     

Angiotensin-converting enzyme gene 2350 G/A polymorphism is associated with left ventricular hypertrophy but not essential hypertension.

The angiotensin-converting enzyme (ACE) gene (ACE) is one of the most studied candidate genes related to essential hypertension (EH) and left ventricular hypertrophy (LVH). ACE rs4343 synonymous coding polymorphism (2350 G/A) is known among the polymorphisms of this gene to have the most significant effect on plasma ACE concentrations. The aim of the present study was to investigate the association of this polymorphism with EH and LVH in 440 subjects (246 EH patients and 194 controls) from a Chinese Han population. In this study, 2350 G/A genotypes were identified by polymerase chain reaction and restriction digestion in all study participants, and left ventricular mass was assessed by 2-mode echocardiography in 178 untreated EH patients. There was no significant difference in either genotype distribution (p=0.3659) or allele frequency (p=0.1453) between EH and control groups. In addition, the 2350 G/A polymorphism had no effect on blood pressure in either controls or untreated EH patients. The distribution of genotypes differed significantly when patients with LVH were examined, i.e., 14.71% GG, 54.41% GA, and 30.88% AA patients had this complication, and 36.36% GG, 42.73% GA, and 20.91% AA patients did not (p=0.0070). The LVH patients had a higher A allele frequency (58.09%) than patients without LVH (42.27%) (p=0.0037). Logistic regression analysis revealed that the association between the A allele and LVH was independent of age, blood pressure, and body mass index. The relative risk of LVH in patients bearing the A allele (GA+AA group) compared with that of GG hypertensive patients was 3.31 (95% confidence interval [CI]: 1.43 to 7.68). These findings suggest an association between LVH and the 2350A allele in hypertensive patients.     

Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphism in coronary disease and malignant ventricular arrhythmias

OBJECTIVES: It has been reported that patients carrying the angiotensin-converting enzyme (ACE) deletion DD genotype with the angiotensin II type 1 (AT1) C allele are at increased risk for myocardial infarction. The frequency distribution of the ACE and AT1 receptor gene polymorphism and their possible relation regarding malignant ventricular arrhythmias in patients with coronary artery disease (CAD) and left ventricular dysfunction was determined. METHODS: The ACE I/D and AT1 A/C polymorphisms (using polymerase chain reaction) in 100 Caucasian patients suffering from CAD with a history of malignant ventricular arrhythmias treated with an implantable cardioverter defibrillator (ICD group) was compared to 127 age-matched Caucasian patients with CAD and no history of malignant ventricular arrhythmias (control group). All patients had reduced left ventricular ejection fraction of < 40% and were comparable regarding sex distribution, body mass index, ACE-inhibitor treatment, lipid status and duration of CAD. RESULTS: The prevalence of DD/CC in the ICD group was significantly higher (19% versus 10%, p < 0.0001). The risk for malignant ventricular arrhythmias was associated with the combination of ACE D and AT1 C alleles (odds-ratio: 2.4, 95% confidence interval 1.41 to 3.94, p < 0.001). The distribution of ACE and AT1 genotypes was not different between the two group. CONCLUSIONS: Patients with coronary artery disease and left ventricular dysfunction carrying ACE D and AT1 C alleles are at increased risk for development of malignant ventricular arrhythmias. Because of available pharmacological inhibitors, these results may have clinical implications for the prevention of sudden cardiac death.     

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.     

Vascular injury in systemic sclerosis: Angiotensin-converting enzyme insertion/deletion polymorphism

The microvascular involvement in systemic sclerosis (SSc) is characterized by endothelial damage and smooth muscle cell migration in the intima. The vascular pathologic modifications in SSc are strikingly similar to those of atherosclerosis. SSc also is characterized by an accelerated macrovascular disease. The gene encoding for angiotensinconverting enzyme (ACE) is a 21-kb, 26-exon gene, localized on chromosome 17 (17q23). Polymorphic sites are an insertion/deletion (I/D) that consists of three genotypes: DD and II homozygotes, and ID heterozygote. ACE gene polymorphisms have been linked to vascular disorders (coronary artery disease, hypertension, cerebrovascular disease, hypertrophic cardiomyopathy, and diabetic or nondiabetic nephropathy). In particular, the possession of ACE D allele was associated with an increased risk of developing malignant vascular injury. ACE D allele frequency of the I/D polymorphism was associated with an increased risk of SSc, suggesting a genetic contribution to the disease. The discrepancy between the high prevalence of D allele and reduced ACE plasma levels in SSc demonstrate the lack of knowledge on the regulation and function of renin-angiotensin system in SSc.