Angiotensin-converting Enzyme Gene Variants Research Articles

Exploring the Relationship between ACE Gene Variants and Systemic Lupus Erythematosus Susceptibility in the Hainan Population through Genetic Association Analysis.

The purpose of this study was to determine the association between single nucleotide polymorphisms (SNPs) at the rs4331, rs4341, and rs4351 loci of the angiotensinconverting enzyme (ACE) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in the Hainan population. This study involved a total of 428 participants, with 214 individuals diagnosed with SLE and an equal number of healthy controls. The SNaPshot sequencing technique was used to determine the base sequences at the ACE gene rs4331, rs4341, and rs4351 loci in the study subjects. Logistic regression was employed to compare the frequency distribution of genotypes and allele frequencies at each locus between the case group and the control group. HaploView 4.2 software was used to analyze the relationship between haplotypes at each locus and genetic susceptibility to SLE. The GG genotype and G allele frequency at the rs4341 locus were higher in the case group compared to the control group. In the rs4341 recessive model, carriers of the GG genotype were more likely to develop SLE compared to carriers of the CG+CC genotype (OR = 1.889, 95% CI: 1.195-2.988, P = 0.006). In the rs4351 overdominant model, carriers of the AC genotype had an increased risk of developing SLE compared to carriers of the AA+CC genotype (OR = 1.514, 95% CI: 1.033-2.219, P = 0.033). The rs4341 and rs4351 loci exhibited linkage disequilibrium, and the CA haplotype (OR = 0.630, 95% CI: 0.481-0.826, P = 0.001) was a protective factor against SLE. The GA haplotype (OR = 2.849, 95% CI: 1.901-4.270, P < 0.01) and the CC haplotype (OR = 2.309, 95% CI: 1.210-4.405, P = 0.009) were risk factors for genetic susceptibility to SLE in the Hainan population. The rs4341 locus of the ACE gene is associated with genetic susceptibility to SLE in the Hainan population.

Impacts of ACE insertion/deletion variant on cardiometabolic risk factors, premature coronary artery disease, and severity of coronary lesions

Angiotensin-converting enzyme (ACE) is closely related to cardiometabolic risk factors and atherosclerosis. This study aims to investigate whether the insertion/deletion (I/D) variant of ACE gene impacts cardiometabolic risk factors, premature coronary artery disease (PCAD), and severity of coronary lesions. PubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until December 22, 2023. 94,270 individuals were included for the analysis. Carriers of DD genotype had higher levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist circumference (WC) than carriers of II or ID genotypes. In addition, carriers of DD genotype were at high risk of PCAD and multiple vessel lesions. The impacts of ACE I/D variant on lipid levels were significant in American individuals but stronger in male individuals. In contrast, the impacts of ACE I/D variant on PCAD and severity of coronary lesions were primarily significant in Caucasian individuals. This study indicates that the ACE I/D variant has a slight but significant impact on cardiometabolic risk factors, PCAD, and severity of coronary lesions. Angiotensin-converting enzyme inhibitors (ACEI) may benefit high-risk populations with ACE DD genotype to prevent PCAD and multiple vessel lesions.PROSPERO registration number: CRD42023426732

Ace gene insertion/deletion polymorphism is associated with glioblastoma in an Iranian population: a case-control study

Background. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has recently been reported to be associated with the pathogenesis and development of human cancers.This study aimed to assess the potential association between ACE (I/D) polymorphism and glioblastoma in an Iranian population.Material and Methods. This case-control study was conducted on 80 patients with glioblastoma and 80 healthy blood donors as controls. Gap-polymerase chain reaction (Gap-PCR) was used to determine the ACE (I/D) genotypes. PCR products were separated and measured by electrophoresis on a 2 % agarose gel.Results. Analysis of demographic data showed a significant difference in the family history of cancer between the case and control groups (p=0.03). The distribution of ACE gene variants including II, ID, and DD genotypes was also calculated, and significant differences were seen in the DD genotype (p=0.03) and D allele (p=0.04) between the glioblastoma cases and controls.Conclusion. ACE gene polymorphism was associated with glioblastoma in the study population. Further studies are needed to approve this finding.

Influence of sex on renin-angiotensin-aldosterone system metabolites and enzymes in Doberman Pinschers.

Estrogen modulates the renin-angiotensin-aldosterone system (RAAS) in women, but sex differences have not been fully explored in dogs. We hypothesized that the RAAS profile of intact female (IF) Doberman Pinschers (DP) would differ from spayed female (SF) and intact male (IM) DP. Eighteen healthy DP (6 IF, 6 SF, 6 IM). Absolute and indexed RAAS metabolites, angiotensin-converting enzyme (ACE) and ACE2 activities, and genotypes (pyruvate kinase dehydrogenase 4, titin, and ACE variants) were compared among sex groups using Kruskal-Wallis or chi-square tests, and linear regression controlling for age. Data are expressed as median (minimum, maximum) and P < .05 was considered significant. The ACE activity was higher in IF DP (656 pmol/L; 436, 784) compared to SF DP (411 pmol/L; 287, 451; P=.01) and IM DP (365 pmol/L; 276, 1200; P=.04) after controlling for age. Angiotensin II, angiotensin I, and plasma renin activity marker (PRA-S) were higher in IF DP compared to SF DP, but not significantly (P ≤ .25). After controlling for age, angiotensin 1-7/angiotensin I was lower in IF DP compared to SF DP (P=.01). Genotypes did not differ among groups. Most DP (94%) were ACE variant positive. Sex and reproductive status influenced the RAAS of DP, with IF DP showing genotype-independent higher ACE activity. These findings hold implications for sterilization practices in female dogs, and support sex and reproductive status as a source of variability in RAAS studies. Additionally, the frequency of the ACE gene variant was very high in this group of DP.

Relationship between Polymorphism of Angiotensin Converting Enzyme Gene with Symptoms of Depression in Schizophrenic Patients

In schizophrenic patients, symptoms of depression are often found which can lead to adverse effects on the treatment process, such as increasing the length of treatment, increasing the possibility of relapse, non-adherence in taking medication, and can also lead to suicide in schizophrenic patients. In schizophrenic patients, the activity of the central angiotensin converting enzyme (ACE) gene is altered and angiotensin II interacts with central dopamine, thereby contributing to the pathophysiology of schizophrenia. In addition, it is likely that the ACE gene variant is also involved in the development of depressive symptoms in schizophrenic patients. This research is a categorical analytic study with a cross sectional method, the sampling method is non-probability sampling with consecutive sampling type, with a total sample of 42 people. There was no significant difference between depression symptoms and ACE gene polymorphisms with P value = 0.746. There was no significant difference between depression symptoms and ACE gene polymorphisms.

Prevalence of an angiotensin-converting enzyme gene variant in dogs

BackgroundGenetic heterogeneity of the canine angiotensin converting enzyme (ACE) gene is functionally important because the degree of aldosterone breakthrough with ACE-inhibitor therapy is greater in variant positive dogs compared to variant negative dogs, but the prevalence of the variant is not known. The purpose of this study was to determine ACE gene variant-positive prevalence in a population of 497 dogs of different breeds.ResultsOverall variant-positive prevalence was 31%, with 20% of dogs heterozygous and 11% of dogs homozygous. The variant was overrepresented in Irish Wolfhounds (prevalence 95%; P < .001), Dachshunds (prevalence 90%; P < .001), Cavalier King Charles Spaniels (prevalence 85%; P < .001), Great Danes (prevalence 84%; P < .001), and Bull Mastiffs (prevalence 58%; P = .02). Irish Wolfhounds were more likely to be homozygous than heterozygous (P < .001).ConclusionsNearly one-third of dogs in this study were positive for a functionally important ACE gene variant, with wide prevalence variability between breeds. The clinical importance of high ACE gene variant-positive prevalence in some breeds requires further study because the highest prevalences were found in breeds that are predisposed to heart disease and therefore may be treated with ACE-inhibitors.

Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic–pituitary–adrenocortical (HPA) axis, which shows hyperactivity in depressed patients. ACE could thus be a promising candidate gene for late-life depression but this has not been examined previously. Depression was assessed in 1005 persons aged at least 65 years, at baseline and over the 10-year follow-up. A clinical level of depression (DEP) was defined as having a score of ⩾16 on the Centre for Epidemiology Studies-Depression scale or a diagnosis of current major depression based on the Mini International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) in the ACE gene were genotyped and diurnal cortisol secretion, as an index of HPA axis activity, was measured. Multivariable analyses were adjusted for socio-demographic and vascular factors, cognitive impairment, and apolipoprotein E. Strong significant associations were found between all seven SNPs and DEP and, in particular, first-onset DEP in persons without a past history of depression (P-values ranging from 0.005 to 0.0004). These associations remained significant after correction for multiple testing. The genotypes that were associated with an increased risk of DEP were also significantly associated with an increase in cortisol secretion under stress conditions. Variants of the ACE gene influence cortisol secretion and appear as susceptibility factors for late-life depression in the elderly population. Whether this could represent a common pathophysiological mechanism linking HPA axis and late-life depression remains to be explored.

Common intronic D variant of ACE gene is associated with endothelial dysfunction in COPD

Pathogenesis of chronic obstructive lung disease (COPD) includes primary inflammatory events, multiple vascular reactions, remodeling of bronchial and vascular walls. The aim of present single-center study was to assess relations between angiotensin-converting enzyme (ACE) gene and prevalence of clinical symptoms characteristic to COPD. The study involved sixty-three male patients with COPD (44-86 years old, a mean of 60.4 years). COPD diagnostics was performed according to common criteria, including evaluation of systolic pressure in pulmonary artery (SPPA) and endothelial disfunction (ED). Genotyping of ACE I/D was performed by means of gene-specific PCR. 1. Allele distribution of studied gene alleles among COPD patients did not differ from control age-matched group. 2. Detectable endothelial dysfunction in COPD patients was shown to correlate with high-producer D allele of ACE gene, at an odds ratio of 6.632 (CI=1.67-26.31; chi2=8.39, p=0.004). Moreover, detectable ED correlated with numbers of COPD exacerbations per year. These findings suggest possible association of the functional ACE D allele with altered vascular responses that may modulate development of distinct COPD symptoms. The results are obtained in a limited clinical cohort, and deserve repeated trials in other groups of COPD patients.

Identification of specific angiotensin‐converting enzyme variants and haplotypes that confer risk and protection against type 2 diabetic nephropathy

Cross-sectional and family studies identified angiotensin-converting enzyme (ACE) gene as a risk factor for diabetic nephropathy (DN). The contribution of ACE gene variants to DN development and progression is controversial and varies among different ethnic/racial groups. We investigated the association of three ACE gene variants with DN, rs1799752 insertion/deletion (I/D), rs1800764T/C and rs12449782A/G in 917 Tunisian type 2 diabetic (T2DM) patients: 515 with (DN) and 402 without (DWN) nephropathy. ACE genotyping was done by PCR-based assays; haplotype estimation was performed using H-Plus software (chi(2)-test based). Genotype frequency distributions of the three studied variants were in Hardy-Weinberg equilibrium. Minor allele frequency of rs1800764 was higher in DN patients than DWN patients or healthy controls, and minor allele frequency of rs1799752 was higher in DN than DWN patients. Higher frequency of rs1799752 and rs1800764 homozygous mutant genotypes was seen in DN compared to DWN patients. Of the three variants, only rs1799752 deletion/deletion (D/D) genotype was associated with a significant increase in albumin to creatinine ratios levels, and D/D carriers had elevated low-density lipoprotein, total cholesterol and urea. Three locus haplotype [rs1799752(I/D)/rs1800764(T/C)/rs12449782(A/G)] analysis revealed that the frequency of DCG haplotype was higher, while that of ITG and ICA haplotypes were lower among unselected type 2 diabetic patients. Taking ITA haplotype as reference, multivariate regression analysis confirmed the negative (ITG), and positive (DCG, DTG, DCA and DTA) association of specific ACE haplotypes with DN, after adjusting for potential nephropathy-linked covariates. Our results support the involvement of specific ACE variants in DN pathogenesis and demonstrate the presence of DN-specific haplotypes at the ACE locus.

Actigenetic of ACE gene polymorphism in Czech obese sedentary females

Obesity is a serious health problem worldwide and many genes have been implicated in determination of obesity, but our knowledge of the genes responsible for individual differences in weight loss after physical intervention are poor. One of the candidate genes is a gene for angiotensin-converting enzyme (ACE) ant its insertion/deletion (I/D) polymorphism. We have analyzed the association between the ACE gene variant in intervened obese females. Twenty four unrelated healthy obese (BMI > 29.9 kg/m(2), with abdominal type of obesity) premenopausal (age between 25 and 45 years) Czech Caucasian sedentary and non-diabetic females, pre-selected according the ACE I/D polymorphism (twelve II and twelve DD homozygotes) were studied in a medical research centre. They underwent 9 weeks intervention program (combination of the lowering of dietary intake to optimal level for the age and 3 times a week physical activity at fitness centre). The participants were supervised to sustain a heart rate of 65 % of maximum. Anthropometrical, biochemical parameters and body composition (Bodystat 1500) were analyzed before and after the intervention. Our study suggest, that in Czech Caucasian females I/D polymorphism within the ACE gene will have no major effect on weight loss. Interestingly, we have detected, that in obese females II genotype was associated with higher increase in basal metabolic rate (202 kcal per day) then in DD homozygotes (p<0.05), thus at least under some circumstances, this genetic variant may have an slight effect on BMI development.

Association of G2350A Polymorphism of Angiotensin Converting Enzyme Gene with Essential Hypertension and Type 2 Diabetes Mellitus in Malaysian Subjects

The objective of this study was to determine the association of Angiotensin-Converting Enzyme (ACE) G2350A polymorphism in Essential Hypertension (EHT) and Type 2 Diabetes Mellitus (T2DM) in Malaysian subjects. A total of 265 samples have been recruited for this study. In order to amplify the 122 bp of G2350A variant of ACE gene, genomic DNA was amplified using Hot-start Polymerase-Chain Reaction (PCR) and the PCR products was digested with BstuI restriction enzyme to produce 103 and 19 bp when A is at position 2350. The subjects were ranged from 30 to 84 years old witi mean age of 51.84 years. The frequency for GG, GA and AA genotypes of ACE gene was 41.43, 48.57 and 10% in EHT, 46.67, 36.67 and 16.66% in T2DM, 32.31, 53.85 and 13.84% in T2DM with EHT compared to 61.43, 35.71 and 2.86% of control subjects respectively. The frequency for A allele of G2350A polymorphism was 34.29% in EHT, 35.00% in T2DM, 40.77% in T2DM+EHT subjects compared to controls (20.71%). The genotype and allele frequency of ACE G2350A gene polymorphism differed significantly in patients when compared to controls (p<0.05). Allele A of G2350A polymorphism of ACE gene is associated with essential hypertension and Type 2 Diabetes Mellitus in Malaysian subjects.

Lack of significant association of an insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene with tropical calcific pancreatitis

BackgroundThe genetic basis of tropical calcific pancreatitis (TCP) is different and is explained by mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene. However, mutated SPINK1 does not account for the disease in all the patients, neither does it explain the phenotypic heterogeneity between TCP and fibro-calculous pancreatic diabetes (FCPD). Recent studies suggest a crucial role for pancreatic renin-angiotensin system during chronic hypoxia in acute pancreatitis and for angiotensin converting enzyme (ACE) inhibitors in reducing pancreatic fibrosis in experimental models. We investigated the association of ACE gene insertion/deletion (I/D) polymorphism in TCP patients using a case-control approach. Since SPINK1 mutations are proposed a modifier role, we also investigated its interaction with the ACE gene variant.MethodsWe analyzed the I/D polymorphism in the ACE gene (g.11417_11704del287) in 171 subjects comprising 91 TCP and 80 FCPD patients and compared the allelic and genotypic frequency in them with 99 healthy ethnically matched control subjects.ResultsWe found 46% and 21% of TCP patients, 56% and 19.6% of FCPD patients and 54.5% and 19.2% of the healthy controls carrying the I/D and D/D genotypes respectively (P>0.05). No significant difference in the clinical picture was observed between patients with and without the del allele at the ACE in/del polymorphism in both categories. No association was observed with the presence or absence of N34S SPINK1 mutation in these patients.ConclusionWe conclude that the ACE insertion/deletion variant does not show any significant association with the pathogenesis, fibrosis and progression of tropical calcific pancreatitis and the fibro-calculous pancreatic diabetes.

Regulation of Steady-state β-Amyloid Levels in the Brain by Neprilysin and Endothelin-converting Enzyme but Not Angiotensin-converting Enzyme

The deposition of beta-amyloid in the brain is a pathological hallmark of Alzheimer disease (AD). Normally, the accumulation of beta-amyloid is prevented in part by the activities of several degradative enzymes, including the endothelin-converting enzymes, neprilysin, insulin-degrading enzyme, and plasmin. Recent reports indicate that another metalloprotease, angiotensin-converting enzyme (ACE), can degrade beta-amyloid in vitro and in cellular overexpression experiments. In addition, ACE gene variants are linked to AD risk in several populations. Angiotensin-converting enzyme, neprilysin and endothelin-converting enzyme function as vasopeptidases and are the targets of drugs designed to treat cardiovascular disorders, and ACE inhibitors are commonly prescribed. We investigated the potential physiological role of ACE in regulating endogenous brain beta-amyloid levels for two reasons: first, to determine whether beta-amyloid degradation might be the mechanism by which ACE is associated with AD, and second, to determine whether ACE inhibitor drugs might block beta-amyloid degradation in the brain and potentially increase the risk for AD. We analyzed beta-amyloid accumulation in brains from ACE-deficient mice and in mice treated with ACE inhibitors and found that ACE deficiency did not alter steady-state beta-amyloid concentration. In contrast, beta-amyloid levels are significantly elevated in endothelin-converting enzyme and neprilysin knock-out mice, and inhibitors of these enzymes cause a rapid increase in beta-amyloid concentration in the brain. The results of these studies do not support a physiological role for ACE in the degradation of beta-amyloid in the brain but confirm roles for endothelin-converting enzyme and neprilysin and indicate that reductions in these enzymes result in additive increases in brain amyloid beta-peptide levels.

Influence of a functional polymorphism within the angiotensin I-converting enzyme gene on partial sleep deprivation in patients with major depression

Partial sleep deprivation (PSD) exerts transient antidepressant efficacy. As a potential mechanism of action an enhancement of dopaminergic neurotransmission within the CNS is discussed. Because genetic variations influencing neurotransmission could have an impact on therapeutic outcome and stability of improvement, we investigated the functional insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene to examine a possible influence on the dopaminergic pathway. We included 56 patients with major depression (DSM-IV). Psychiatric ratings including the HAM-D6 scale were assessed prior to and after PSD and related to the different genotypes. The ACE I/D polymorphism was determined following PCR amplification using genomic DNA. A total of 58.1% of the patients were PSD responders. As expected, the therapeutical effect of PSD was transient and most patients experienced an exacerbation of depressive symptoms on day 2. Subdivision according ACE gene variants showed a significantly less pronounced relapse of symptoms in ACE gene D-allele carriers ( P=0.02). Our results give first hints that the ACE I/I genotype, probably influencing dopaminergic neurotransmission, could be an indicator for relapse after PSD. This should result in earlier and more intense additional therapeutic interventions in this group of patients.

Bradykinin B2BKR receptor polymorphism and left-ventricular growth response

Angiotensin-converting-enzyme (ACE) activity regulates left-ventricular growth. The deletion (D), rather than the insertion (I), ACE gene variant is associated with increased ACE activity and kinin degradation, and the absence (-) rather than the presence (+) of a 9 bp deletion in the gene encoding the bradykinin 2 receptor (B2BKR) is associated with greater gene expression. We determined the ACE and B2BKR genotype of 109 male army recruits, and measured their physiological left-ventricular growth response to a 10-week physical training programme. Mean left-ventricular growth was 15.7 g (SE 3.5) in those with ACE genotype D/D and B2BKR genotype +9/+9, but -1.37 g (4.1) in those with ACE genotype I/I and B2BKR genotype -9/-9 (p=0.003 for trend across genotypes). These results suggest that kinins regulate left-ventricular growth, mediating some of the effects of ACE in this regard.

An angiotensin-converting enzyme gene variant is associated with acute myocardial infarction in women but not in men

We believe our data may speak to the issue of sexual dimorphism with respect to MI. Most studies have concentrated on men with this disease. In a recent study, Lindpaintner et al 10 could find no relationship between the D/D genotype and AMI in subjects of the Physicians Health Study. However, this study consisted entirely of men. The D allele may provide an avenue to discern differences in the pathogenesis of MI in men and women.

Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy

Summary Polymorphism in the angiotensin-converting enzyme (ACE) gene has been shown to correlate with circulating ACE concentrations, and also to be an independent risk factor for the development of myocardial infarction, particularly in men thought to be at low risk by standard criteria. We determined the genotypes of individuals with end-stage heart failure due to either ischaemic dilated cardiomyopathy (102) or idiopathic dilated cardiomyopathy (112) and compared these to organ donors with normally functioning hearts (79). Genotypes were determined by the polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene to amplify template DNA isolated from patients. Compared with the DD frequency in the control population, the frequency of the ACE DD genotype was 48% higher in individuals with idiopathic dilated cardiomyopathy (p=0·008) and 63% higher in subjects with ischaemic cardiomyopathy (p=0·008), suggesting that an ACE gene variant may contribute to the pathogenesis of both types of cardiomyopathy.