non-DD Genotype Research Articles

DD genotype of the I/D Angiotensin-Converting Enzyme Gene Polymorphism is a higher Risk for Atopic Asthma

Background: Atopic asthma begins with exposure to allergens causing airway hyperresponsiveness and chronic inflammation. Angiotensin II involved in the pathogenesis of atopic asthma by causing airway hyperresponsiveness. Angiotensin II levels are influenced by the levels of ACE and ACE levels are influenced by I / D ACE gene polymorphisms. Study about the role of I/D ACE gene polymorphism in the incidence and severity of asthma in several countries and etnic showed inconsistency result. Study in Indonesian subjects had never been reported. Method: This Case-control study aimed to evaluate influence of I/D ACE gene polymorphism in incidence and severity of atopic asthma. Eighty subjects aged 15-50 years including Forty non–asthmatic and Forty atopic asthmatic patients were included in this study.. Result: DD genotype with atopic asthma (85.7%) was higher than non atopic asthma (14,3%). Non-DD genotype (ID,II) with atopic asthma (46.6%) was lower than atopic asthma (53.4%). DD genotype of the ACE gene had risk 6.8 times to become atopic asthma than non-DD genotype (OR=6.8,p=0.05). DD genotype of ACE gene was not a risk factor for severe obstruction (OR=0.50, p=0.48) and uncontrolled atopic asthma compared to non-DD genotype (OR = 1.8,p=0.49) Conclusions: This study concluded that DD genotype of ACE gene was a risk factor for the incidence of atopic asthma but not a risk factor for severe obstruction and uncontrolled atopic asthma.

Correlations between ACE single nucleotide polymorphisms and prognosis of patients with septic shock.

The aim of the present study is to investigate association between septic shock (SS) and angiotensin I-converting enzyme (ACE) single nucleotide polymorphisms (SNPs). From October 2009 to December 2016, 238 SS patients and 242 healthy individuals were selected for our study. ACE activity was detected, ACE rs4291 and rs4646994 polymorphisms were detected using PCR-restriction fragment length polymorphism (PCR-RFLP). The Kaplan–Meier survival curve was employed to evaluate the association between ACE SNPs and patients’ survival and univariate and multivariate analyses to estimate risk factors for SS. ACE activity in the case group was increased in comparison with the control group. Allele and genotype frequencies of rs4291 and rs4646994 were different between the case and control groups. The TT genotype frequency of the rs4291 polymorphisms and the DD genotype of the rs4646994 polymorphisms of the case group were higher than those in the control group. The AT and TT genotypes indicated a significant elevation of ACE activity than the AA genotype, while a significant decline was found in the DI and II genotypes in comparison with the DI genotype. Patients with TT or DD genotypes had increased fatality rate within 7 and 30 days when compared with those with non-TT or non-DD genotypes. Lower sepsis-related organ failure assessment (SOFA) scores, rs4291, serum ACE and rs4646994 were all considered as risky factors for SS patients. The study demonstrates that TT genotype of rs4291 or DD genotype of rs4646994 may be indicative of a higher risk of SS and a poorer prognosis in SS patients.

The link between angiotensin-converting enzyme genotype and pulmonary artery pressure in patients with COPD

The insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of cardiovascular diseases. In patients with primary pulmonary hypertension, the homozygous ACE DD genotype is more prevalent than the non-DD genotype. However, the relationship of ACE gene polymorphism to secondary pulmonary hypertension remains unclear, and ethnicity may be one of the factors that can modulate the effects of ACE genotypes reported in different studies. We hypothesized that in patients with chronic obstructive pulmonary disease (COPD) the presence of the D allele in the ACE gene polymorphism is associated with increased pulmonary artery pressure (Ppa). Bodyplethysmography was used to assess lung function in 66 consecutive patients with COPD; pulmonary artery pressures were determined using echocardiography. ACE gene I/D polymorphism was identified with the polymerase chain reaction. 118 healthy persons served as the control group. All patients and controls were Caucasian. Genotype II was identified in 15 patients with COPD, genotype ID in 31 and genotype DD in 20. In the control group, genotype II was identified in 19 persons, genotype ID in 68 and genotype DD in 31. The distribution of ACE gene polymorphism did not differ between patients and the control group. In patients with COPD, no differences were seen between the three genotype groups in mean age, smoking history, hemoglobin concentrations or ventilometric or blood gas variables. Both systolic and mean Ppa differed significantly between the II, ID and DD groups (Systolic Ppa: 24.4 +/- 2.2 versus 31.3 +/- 2.5 and 36.7 +/- 3.9 mm Hg, respectively, ANOVA, p < 0.05; Mean Ppa: 13.0 +/- 1.5 versus 17.5 +/- 1.4 and 21.2 +/- 2.8 mm Hg, respectively, ANOVA, p < 0.05). In multiple linear regression analysis, the I/D ACE gene polymorphism (p < 0.05), SaO2 (p < 0.05) and the duration of COPD (p < 0.02) were independent predictors of systolic and mean Ppa. The results of the study suggest that I/D ACE gene polymorphism is linked to pulmonary artery pressure in Caucasian patients with COPD.

ANGIOTENSING CONVERTING ENZIME (ACE) MRNA EXPRESSION IN PROTOCOL BIOPSIES WITH CHRONIC ALLOGRAFT NEPHROPATY (CAN)

P291 Although chronic allograft nephropathy (CAN) is a multifactorial disease, it has been suggested that the renine-angiotensin system (RAS) could have a critical role in its development. The key reaction in the RAS pathway is catalysed by the angiotensing-converting enzime (ACE), and their blockade has been shown to improve the prognosis of several chronic nephropathies. Aims: The main aim of this study was to analyse the association among kidney allograft lesions and ACE renal levels. Moreover, since the DD polymorphism of the ACE gene has been associated with a poor kidney survival, we also studied the role of DD genotype in ACE mRNA expression. Methods: ACE genotype and ACE mRNA levels were determined in 64 protocol biopsies from the same number of transplanted patients. Results: ACE mRNA levels were not related to the ACE genotype, and did not depend on the severity of the allograft lesions, as classified according to the Banff squema. In patients displaying the DD genotype ACE mRNA levels were correlated with proteinuria (R=0.51, p=0.012), and were higher in allografts with chronic vascular lesions than in patients without vascular involvement (vasculopathy: n=4, 1.38 ± 0.97, no vasculopathy: n=19, 0.36±0.65, p=0.016). In patients with non-DD genotypes, ACE levels were correlated with mean arterial pressure (R=0.3, p=0.055). Finally, we observed an association among ACE levels in DD-patients and the immunossupressive treatment used. Thus, DD patients displayed higher ACE levels than non-DD patients only when treated with Csa (DD: n=11, 0.89±1.04 vs no-DD: n=16, 0.064 ±0.68, p=0.019), and not when treated with tacrolimus. Conclusions: In DD-patients, renal ACE levels correlated with proteinuria, and increased with Csa treatment and with chronic vascular lesions. Treating patients displaying CAN and vasculopathy with ACEI or ARAII should improve their prognosis.

Effects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure

Background Angiotensin-converting enzyme (ACE) is involved in the pathophysiology of chronic heart failure, and its activity is determined in part by a polymorphism of the ACE gene. We hypothesized that the benefits of spironolactone, which inhibits downstream elements of ACE-mediated abnormalities, may depend on ACE genotype. Methods We randomly assigned 93 chronic heart failure patients to treatment with spironolactone (n = 47) or to a control group (n = 46) and followed them for 12 months. Genotype for the insertion/deletion polymorphism of the ACE gene was determined by polymerase chain reaction. An echocardiographic examination was performed at baseline and at the end of the 12 months. Results The mean (± SD) age of the 93 patients was 62 ± 9 years, and the mean New York Heart Association class was 2 ± 1. The genotype was DD in 26 patients (28%). Forty-seven patients were assigned to spironolactone treatment (mean dose, 32 ± 16 mg). In the treated group, only patients with a non-DD genotype showed significant improvement in left ventricular ejection fraction (3.0%; 95% confidence interval [CI]: 1.2% to 4.8%; P = 0.002), end-systolic volume (–23 mL; 95% CI: –36 to –11; P = 0.0005), and end-diastolic volume (–27 mL; 95% CI: –43 to –12; P = 0.001). In the multivariate analysis, the estimated net effect of treatment was 29 mL better (95% CI: –20 to 78 mL) for end-diastolic volume, 20 mL better (95% CI: –18 to 58 mL) for end-systolic volume, but 1.4% worse (95% CI: –3.4% to 6.2%) for left ventricular ejection fraction in patients with non-DD versus DD genotypes. Conclusion The effects of spironolactone treatment on left ventricular systolic function and remodeling may in part depend on ACE genotype.

Angiotensin-1 converting enzyme polymorphisms in chronic beryllium disease.

To test the hypothesis that the angiotensin converting enzyme (ACE) genotype is associated with chronic beryllium disease (CBD) and disease severity, we studied 50 cases of CBD and compared their ACE genotype to that of two different control groups, consisting of: (1) 50 participants from a beryllium machining facility; and (2) 50 participants from a non-beryllium-associated workplace. We found no statistically significant difference in the frequency of the I or D allele or of the DD genotype among cases of CBD and either control group. The odds ratio (OR) for the CBD DD genotype as compared with the non-DD genotype was 1.58 (95% confidence interval [CI]: 0.68 to 3.66, p = 0.12) for the beryllium-exposed control group, and 1.09 (95% CI: 0.48 to 2.46, p = 0.56) for the non-beryllium-exposed controls. We found an association between serum ACE activity and the ACE genotype, with DD cases having the highest median serum ACE activity (p = 0.005). We evaluated the beryllium lymphocyte proliferation test (BeLPT), bronchoalveolar lavage (BAL) cell components, chest radiography, pulmonary function test results, and exercise physiology in our CBD cases. No statistically significant associations with these disease markers were found for the CBD cases with the DD genotype. Although the difference was not statistically significant, the DD cases had a shorter median duration of exposure to beryllium before diagnosis of CBD, and tended to have a weaker response in their blood and BAL BeLPT than did the non-DD cases. These findings may indicate that the ACE genotype is important in the immune response to beryllium and in progression to beryllium disease.

Influence of cardiovascular risk factors on relation between angiotensin converting enzyme-gene polymorphism and blood pressure in arterial hypertension.

The angiotensin-converting enzyme gene insertion (I)/deletion (D) polymorphism might be involved in the development of several cardiovascular diseases, but its role in humans remains controversial. To investigate the relation between the angiotensin converting enzyme gene polymorphism and extent of blood pressure elevation in arterial hypertension, taking into account the influence of cardiovascular risk factors. We studied 171 patients (aged 49 +/- 9 years, 61 women) with abnormal clinic and 24 h ambulatory blood pressures, after a 3-week wash-out. We found no significant difference in clinic and ambulatory blood pressures among homozygotic D (DD), heterozygotic D (ID) and homozygotic I (II) angiotensin converting enzyme genotypes and between homozygotic D (DD) and pooled heterozygotic D (ID) plus homozygotic I (II) (non-DD) angiotensin converting enzyme genotypes. At least one additional cardiovascular risk factor (smoking, hypercholesterolaemia or diabetes) was present for 103 patients (33 DD and 70 non-DD). Non-DD subjects (n = 43) without additional cardiovascular risk factors exhibited lower values of 24 h, daytime systolic and pulse blood pressures than did members of all other groups (all P < 0.04). In the presence of risk factors, DD and non-DD subjects exhibited similar systolic and pulse ambulatory blood pressures, in that we found higher values in non-DD genotype subjects with risk factors than we did for non-DD subjects without additional risk factors. In multivariate analysis, the combination of non-DD genotype and absence of cardiovascular risk factors was associated with the lowest values of systolic and pulse blood pressures. Angiotensin converting enzyme insertion allele appears clustered with lower ambulatory systolic and pulse blood pressures in hypertensive patients when the potential interference of additional cardiovascular risk factors is eliminated. A high prevalence of cardiovascular risk factors in population studies might blunt a possible biological association of blood pressure with DD genotype by contributing to raising of blood pressures also in subjects with non-DD genotypes.

DD genotype of the angiotensin I-converting enzyme gene is a risk factor for early onset of essential hypertension in Japanese patients

Although angiotensin-converting enzyme (ACE) plays an important role in blood pressure regulation, no relationship between the insertion/deletion (I/D) polymorphism of the ACE gene and essential hypertension has been observed. However, as the pathogenesis and genetic background of essential hypertension are heterogeneous, we investigated whether the ACE gene is a marker of subgroups of patients with essential hypertension. A group of 178 patients with essential hypertension (90 men/88 women; 53 ± 13 years of age, mean age ± SD) and 101 normotensive control subjects (54 men/47 women; 51 ± 14 years of age, mean age ± SD ) were included in the study. The allele frequencies of the two groups were similar. There were no differences in age, blood pressure, retinopathy grade, presence of proteinuria, or resting plasma renin activity (PRA) among the hypertensive patients with the II, ID, and DD genotypes. However, the age of onset of hypertension of patients with the DD genotype was lower ( p < 20.05) and their left ventricular mass index was higher ( p < 20.05) than those in patients with the non-DD genotype. These data suggest that the I/D polymorphism of the ACE gene is associated with an early onset of hypertension and left ventricular hypertrophy in Japanese patients with essential hypertension.

U.K. Prospective Diabetes Study XV: Relationship of renin-angiotensin system gene polymorphisms with microalbuminuria in NIDDM

We performed a case-control study to determine whether molecular variants of genes of the renin-angiotensin system were associated with the presence of albuminuria in non-insulin dependent diabetes mellitus (NIDDM). A total of 180 diabetic patients with persistent microalbuminuria [median urinary albumin (interquartile range) of 74 (54 to 126 mg/liter)] were matched with two control groups of diabetic patients without microalbuminuria [median urinary albumin 7 (5 to 10) mg/liter] for variables known to be associated with raised urinary albumin concentration including hemoglobin A1c and triglyceride. One control group was also matched for blood pressure and the other group was not, to allow assessment of interactions with hypertension. Association with the I/D polymorphism of the ACE gene and M235T variant of the angiotensinogen gene (AGT) with microalbuminuria and retinopathy was examined. There were no significant differences in genotype frequency between cases and controls for ACE or AGT irrespective of blood pressure matching. However, among subjects with microalbuminuria, those with the ACE DD genotype had a significantly greater urinary albumin excretion than individuals with a non-DD genotype [median 88 (68 to 170) mg/liter vs. 67 (53 to 113) mg/liter, P < 0.001]. More subjects with the DD than non-DD genotype had persistent albuminuria > 100 mg/liter, twice the upper normal range (60% vs. 38%, P = 0.006). When increased albumin excretion occurs, the presence of the ACE DD genotype appears to be associated with higher urinary albumin levels. No association with retinopathy was observed.

Importance of angiotensin-converting enzyme in pulmonary hypertension.

Angiotensin II causes pulmonary vasoconstriction in man and in animals, and angiotensin-converting enzyme (ACE) inhibitors have prevented the development of chronic pulmonary hypertension in animals models. Angiotensin II may contribute to lung vascular remodeling in pulmonary hypertensive disease, since cilazapril, an inhibitor of ACE, reduces pulmonary vascular medical thickening in chronically hypoxic rats with established pulmonary hypertension. Furthermore, the ACE DD genotype, which has been associated with increased circulating and tissue ACE activity, has been associated with left ventricular hypertrophy in human hypertensive disorders. The ACE DD genotype may also 'permit' a greater hypertrophic adaptation of the pressure-over-loaded right ventricle. In fact, we have shown that pulmonary hypertension patients with maintained cardiac output and less right-heart failure fall into the group with the DD genotype and that patients with a low cardiac output and more severe right-heart failure fall into the group with the non-DD genotype, supporting the hypothesis. We assessed cardiopulmonary hemodynamics in patients with primary (unexplained) pulmonary hypertension and segregated the patients based on their ACE genotype. For similar mean pulmonary artery pressures in the DD and non-DD groups, the cardiac output was substantially lower in the patients with the non-DD genotype, whereas the values for mean right atrial pressure and pulmonary vascular resistance were double when compared with the DD group. Our data show that the ACE DD genotype is prevalent in patients with severe pulmonary hypertension and is a marker of maintained right ventricular function.