Angiotensin-converting Enzyme Deletion Allele Research Articles

Influence of genetic polymorphisms in vascular endothelial-related genes on the clinical outcome of axitinib in patients with metastatic renal cell carcinoma

ABSTRACT Objective Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients. Methods This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function. Results Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p = .045 and p = 0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p = .025 and p = 0.036, respectively). Conclusions Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

Identification of genetic markers for skill and athleticism in sub-elite Australian football players: a pilot study.

Natural genetic variation contributes towards athletic performance in various strength/power and endurance based sports. To date, no studies have explored the genetic predisposition towards skill and athletic performance in Australian Football (AF) players. The present pilot study recruited 30 sub-elite AF players who completed tests of endurance, power and technical skill. Specific polymorphisms in nine genes were screened, and assessed for a possible association with athletic and skill traits. Statistical analysis using generalized linear models identified a number of polymorphisms predictive of endurance and technical skill. The angiotensin-converting enzyme (ACE), normally responsible for regulation of body fluid volume, was a significant factor in predicting 'all round' athletic performance and skill. Specifically, the deletion allele (DD) of ACE was identified as a predictor for AF power (P≤0.008), endurance (P=0.001) and skill assessments (P≤0.003). In addition, polymorphisms in the brain-derived neurotrophic factor, D2 dopamine receptor, and catechol-O-methyltransferase genes were also shown to contribute to kicking skill outcomes (P≤0.044). This is the first study to implicate the ACE deletion allele for a multidimensional sport in such a way. Further, the results from this study have identified several new candidate genes in predicting athletic and technical skill outcomes.

Maternal Deletion Allele of Angiotensin-Converting Enzyme Gene is Associated with Fetal Growth Restriction

To investigate the correlation between maternal and fetal angiotensin-converting enzyme gene insertion or deletion polymorphism and birth size, angiotensin-converting enzyme gene insertion or deletion polymorphisms of 470 Japanese pairs of mothers and infants were genotyped. The relationships between maternal and fetal angiotensin-converting enzyme gene insertion or deletion polymorphisms and birth sizes (weight, length, head circumference, and the incidence of small-for-gestational age status) were analyzed. No relationship between fetal angiotensin-converting enzyme genotype and birth size was observed. In contrast, the incidence of small-for-gestational age status in babies whose mothers had 1 or 2 deletion alleles was greater than that in babies whose mothers had 2 insertion alleles (7% vs 3%, P = 0.045). Maternal deletion allele of angiotensin-converting enzyme is associated with fetal growth restriction in the Japanese normal population.

Angiotensin-converting enzyme deletion allele is beneficial for the longevity of Europeans

The human angiotensin converting enzyme (ACE) gene is one of the most investigated candidate genes for cardiovascular diseases (CVD), but the understanding of its role among the elderly is vague. Therefore, this study focuses at: (a) testing the association of ACE polymorphism with CVD risk factors among the elderly, and (b) detecting the possible unequal distribution of ACE genotypes between senescent and younger segments of the European populations. The association of ACE I/D polymorphism with CVD health status [hypertension (HT), obesity, dislypidemia] in 301 very old subjects (88.2 ± 5 years; F/M = 221/80) was tested by means of logistic regression analysis. The meta-analysis of D allele frequency in general vs. elderly (80+ years) groups was conducted using all publicly available data for European populations comprising both age cohorts. Multiple multinomial logistic regression revealed that within this elderly sample, age (younger olds, 80-90 years), female sex (OR = 3.13, 95% CI = 1.59-6.19), and elevated triglycerides (OR = 2.53, 95% CI = 1.29-4.95) were positively associated with HT, while ACE polymorphism was not. It was also established that the DD genotype was twice as high in 80+ cohort compared to general population of Croatia (p < 0.00001). This trend was confirmed by the meta-analysis that showed higher D allele frequencies in olds from nine of ten considered European populations (OR = 1.19, 95% CI = 1.08-1.31). The data in elderly cohort do not confirm previously reported role of ACE DD genotype to the development of HT. Moreover, meta-analysis indicated that ACE D allele has some selective advantage that contributes to longevity in majority of European populations.

The Association of Angiotensin Converting Enzyme (ACE) Polymorphisms with Sleep Apnea and Hypertension

To identify the role of polymorphisms in the angiotensin-converting enzyme (ACE) gene in modulating susceptibility to hypertension in sleep apnea. Observational cross-sectional study. Nine hundred seventy-two participants of the Cleveland Family Study who underwent home sleep studies, blood pressure assessments, and genotyping. After controlling for age, sex, race, and obesity, hypertension risk was reduced in participants who possess the ACE deletion (D) polymorphism with an odds ratio = 0.63 (95% confidence interval: 0.41-0.96) comparing those with 2 versus no D alleles. In analyses stratified by apnea severity, the protective effect of the D allele was most evident in those with severe apnea. Among subjects with severe apnea, the odds ratios for hypertension were 0.47 (0.22-1.00) for 1 D allele and 0.57 (0.26-1.24) for 2 D alleles. The ACE deletion allele may protect against hypertension in the setting of obstructive sleep apnea. Further research into the potential role of angiotensin in modulating the hypertensive effect of sleep apnea is needed.

Deletion Allele of Angiotensin-Converting Enzyme is Associated with Increased Risk and Severity of Bronchopulmonary Dysplasia

To explore whether the deletion (D) allele of angiotensin-converting enzyme (ACE) is associated with the risk or severity of bronchopulmonary dysplasia (BPD) among very low birth weight (BW) infants. Infants with a BW < or = 1250 g were prospectively recruited. The D and I (insertion) alleles of ACE were determined using a polymerase chain reaction followed by restriction fragment length polymorphism analysis. Infants with DD/DI genotype of ACE had a (mean +/- SD) birth weight (938 +/- 204 g vs 925 +/- 196 g) and gestational age (28 +/- 3 weeks vs 28 +/- 2 weeks), similar to infants with II genotype of ACE (P > .05). Infants with DD/DI genotype of ACE were more likely to have BPD than infants with II genotype (47% vs 22%, P = .025). Among infants with BPD, ACE DD/DI genotype was more common among infants with moderate or severe BPD compared with infants with mild BPD (74% vs 26%, P = .012). The number of D alleles of ACE correlated directly and positively with the severity of BPD (R = 0.23, P = .045). The D allele of ACE is associated with an increased risk and severity of BPD among preterm infants.

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

We evaluated the interaction of angiotensin-converting enzyme (ACE) inhibitor therapy with the effect of the ACE D/I polymorphism on heart failure survival. The ACE deletion allele, ACE-D, is associated with increased ACE activity. The utilization of ACE genotyping to predict the impact of ACE inhibitor dose has not been previously evaluated. We prospectively studied 479 subjects with systolic dysfunction (left ventricular ejection fraction 0.25 +/- 0.08). Subjects were divided on the basis of ACE inhibitor therapy into low dose (<or=50% of target dose, n = 227), standard (high) dose (>50%, n = 201), or those receiving angiotensin receptor antagonists (n = 51). Patients were genotyped for the ACE D/I polymorphism, followed to the end point of death or cardiac transplantation, and transplant-free survival compared by genotype. The ACE-D allele was associated with an increased risk of events (p = 0.026). In analysis by ACE inhibitor dose, this effect was primarily in the low-dose group (1-year percent event-free survival: II/ID/DD = 86/77/71,2-year = 79/66/59, p = 0.032). In the standard-dose group, the impact was markedly diminished (1-year: II/ID/DD = 91/81/80, 2-year: 77/70/71, p = 0.64). The impact of beta-blockers and high dose ACE inhibitors was greatest in subjects with the ACE DD genotype (p = 0.001) and was less apparent with the II and ID genotypes (p = 0.38). Higher doses of ACE inhibitors diminished the impact of the ACE-D allele, and the benefits of beta-blockers and high-dose ACE inhibitors appeared maximal for DD patients. Determination of ACE genotype may help target therapy for patients with heart failure.

Interaction of Implantable Defibrillator Therapy with Angiotensin‐Converting Enzyme Deletion/Insertion Polymorphism

The angiotensin-converting enzyme deletion allele (ACE D) decreases survival in patients with advanced heart failure. Whether the adverse impact on survival reflects an increased risk of pump failure or arrhythmic sudden death remains uncertain. If the ACE D genotype increases the risk of sudden death, implantable cardioverter defibrillator (ICD) therapy should diminish its negative impact. We sought to evaluate the effect of ICD therapy on ACE D genetic risk. The Genetic Risk Assessment of Cardiac Events (GRACE) study enrolled 479 patients at the University of Pittsburgh between 1996 and 2001. Blood was genotyped for the ACE D/I (deletion/insertion) polymorphism. Of the 479 patients, 82 (77% male, 84% Caucasian, age 56 +/- 11 years, 60% ischemic, left ventricular ejection fraction 0.23 +/- 0.08) received an ICD and were selected for outcomes analysis (mean follow-up 871 +/- 538 days). Transplant-free survival and survival alone were compared in ACE DD patients (n = 24, 29%) versus ACE DI/II patients (n = 58, 71%). Survival was significantly improved in ACE DI/II patients compared to those without an ICD (1 year: 93% vs 87%; 2 year: 89% vs 77%; P = 0.02) but not in ACE DD patients. Transplant-free survival among patients with an ICD was significantly worse in ACE DD versus ACE DI/II (1 year: 67% vs 88%, 2 year: 55% vs 80%, P = 0.03). Analysis of survival as a single endpoint revealed a similar result (1 year = 78% vs 94%; 2 year: 72% vs 88%; P = 0.05). ICD telemetry data showed a nonsignificant trend toward fewer individuals with arrhythmias in the ACE-DD group (46% vs 65%, P = 0.22) ICDs do not diminish the adverse influence of the ACE DD genotype on survival. This finding suggests that mortality in this high-risk genetic subset of patients is due to progression of heart failure rather than arrhythmic sudden death.

Angiotensin converting enzyme deletion allele in different kinds of dementia disorders

In order to verify the association of Angiotensin converting enzyme (ACE) gene with different kinds of dementia, as well as its association with APO-E (genotype), we performed ACE genotyping in subjects with late-onset probable Alzheimer's disease (LOAD, n=64), early-onset probable Alzheimer's disease (EOAD, n=32), possible Alzheimer's disease (pAD, n=44), vascular dementia (VD, n=12), age-associated memory impairment (AAMI, n=15) and 40 healthy age-matched controls, who were previously characterized for APO-E. After the principal component analysis ACE D and Apo-Eϵ 4 alleles disclosed the highest prevalence in the cognitively impaired groups of subjects, Apo-Eϵ 4 being more specific for LOAD and pAD. ACE D allele seems to be an unspecific susceptibility factor for mental decline.

ACE insertion/deletion genotype affects bradykinin metabolism.

A deletion allele of the angiotensin-converting enzyme (ACE) gene has been associated with increased serum ACE activity, enhanced conversion of angiotensin (Ang) I to Ang II, and cardiovascular morbidity. This study tested the hypothesis that the ACE deletion allele is also associated with enhanced degradation of bradykinin, a vasoprotective peptide. Metabolism of synthetic bradykinin was measured in sera obtained from subjects who were homozygous for either the ACE deletion (n=12) or insertion (n=8) allele and who had participated in an Ang I-infusion protocol. ACE levels tended to be increased in subjects who were DD compared with those who were II [41.2 (95% CI, 27.9, 54.3) vs. 28.0 IU/L (20.0, 35.9); t=-1.6; p=0.1 18]. During Ang I infusion, plasma Ang II concentrations were increased in DD compared with II subjects (F =4.4; p=0.052). In contrast, the half-life of bradykinin was significantly decreased in sera obtained from ACE DD compared with II subjects [26.3 s (17.8, 34.6 s) vs. 42.1 s (24.4, 59.9 s); t=-2.4; p=0.029]. Moreover, there were significant inverse relations between the half-life of bradykinin and serum ACE activity (p < 0.001) and between the half-life of bradykinin and the conversion of Ang I to Ang II (p=0.026). This study confirms that ACE genotype determines bradykinin degradation and suggests another mechanism whereby the ACE D allele could be associated with deleterious cardiovascular effects.

Angiotensin-converting enzyme deletion polymorphism is associated with hypertension in a Sikh population.

The deletion polymorphism, situated in intron 16, of angiotensin-converting enzyme (ACE) gene (17q23) has been observed to be associated with an increased risk for myocardial infarction and left ventricular hypertrophy in Caucasian populations. The homozygous genotype for the deletion allele (DD) has additionally been observed at greater frequencies in hypertensive individuals of African-American and Japanese origin. In a population-based study of a Sikh population, we compared the occurrence of the insertion/deletion polymorphism at the ACE gene in subjects with hypertension to those with normal blood pressure. The ACE deletion allele was observed with a greater frequency in hypertensive subjects than in the normotensive subjects (p < 0.0001). These findings raise the possibility that in some ethnic subgroups, variation in or near the ACE gene may contribute to the development, and severity, of hypertension.