Prédisposition génétique à la néphropathie diabétique: rôle du polymorphisme I/D du gène ACE / Genetic Predisposition to Diabetic Nephropathy: Role of I/D ACE Gene Polymorphism

Introduction - La néphropathie diabétique est la principale cause de la maladie rénale chronique et représente la complication la plus fréquente et la plus grave du diabète. Sa pathogénie exacte est complexe et noncomplètement élucidée. Plusieurs facteurs et mécanismes contribuent au développement et à l'issue de cette pathologie. Les objectifs de notre travail sont de déterminer la fréquence du polymorphisme Insertion(I)/Délétion (D) du gène ACE (angiotensin-converting enzyme) chez des patients diabétiques avec et sans néphropathie et d'établir la relation entre ce polymorphisme et la néphropathie diabétique dans une population de l'Est algérien. Matériel et Méthodes - Nous avons recruté à cet effet, vingt neuf sujets diabétiques avec néphropathie et trente témoins diabétiques sans néphropathie. L'extraction de l'ADN a été réalisée sur du sang frais par la méthode au NaCl et le polymorphisme I/D du gène ACE a été déterminé par PCR (polymérase Chaine Réaction). Un consentement éclairé a été obtenu de l'ensemble des participants. Résultats - La durée moyenne du diabète chez noscas est de 19,21 ± 9,31ans ; celle des témoins est de 10,67 ± 7,66 ans. Le diabète de type 1 est plus fréquent chez les néphropathes (72,41%), chez les témoins la fréquence du diabète de type 2 est plus importante (73.33%). Les complications macro-angiopathiques sont plus prévalentes chez les néphropathes. De plus l'association de deux ou plusieurs complications est fréquemment retrouvée. Les fréquences des allèles I et D sont respectivement 13,79 % et 86,21 % chez les sujets témoins alors que les fréquences alléliques chez les sujets avec néphropathie sont respectivement 19,64 % et 80,36 %. Conclusion - Aucune association significative entre ce polymorphisme et la néphropathie diabétique n'a été démontrée.

Role of Angiotensin Converting Enzyme (ACE) Gene Polymorphism in Breast Cancer among North Indian Population

Background: The most common cause of cancer related death among women in the world is Breast cancer (BCa). Almost Every year, approximately 1,300,000 cases and 450,000 deaths are related with Carcinoma of Breast are reported worldwide. The incidence of invasive Carcinoma of Breast and mortality in American women in 2017 was 252,710 and 40,610 respectively as quoted by a study. According to latest survey conducted by the Indian Council of Medical Research (ICMR) in India, there were an estimated 150,000 new cases of Carcinoma of Breast in the year 2016. The rise in both Carcinoma of Breast incidence and mortality, therefore, necessitates an examination of risk factors associated with this disease. Molecular subtypes-based classification system characterized by the presence or absence of immunohistochemical expressions like Progesterone receptor (PR), Estrogen receptor (ER), and Human epidermal growth factor receptor 2 (HER2) may show certain limitations. The gene encoding ACE (Angiotensin Converting Enzyme,) in humans is located in the chromosome 17 (17q23), consisting of 26 exons and 25 introns and spanning 21 kb. ACE is a zinc dependent dipeptidyl carboxypeptidase which catalyzes conversion of inactive decapeptide Angiotensin I (Ang I) to active octapeptide Ang II . Ang II mediates physiological effects by binding to two subtypes of the receptors, AGTR1 and Angiotensin II receptor type II (AGTR2), which belongs to superfamily of G-protein-coupled receptors (GPCRs).So, keeping all these physiological effects in mind, this study was conducted to see the role of ACE gene in carcinoma of breast. Methods: From confirm and control cases 3.0 ml of venous blood from each study subject was collected in an EDTA vial. Genomic DNA was extracted by phenol-chloroform method. The genotyping was performed by using PCR (Polymerase Chain reaction), using gene-specific primers. The resulting PCR products were separated on 2% agarose gels using ethidium bromide stain and visualized under UV light. The clinicopathologic parameters of breast cancer patients were obtained from medical records. Results: Of the 10 patients, 3 (30%) had Deletion/deletion genotype DD, 6 (60%) had ID, and 1 (10%) had II genotypes. In control subjects, 2 (20%) had DD, 6 (60%) had ID, and 2 (20%) had II genotypes. Conclusion: The results showed no significant association of ACE gene polymorphism with breast cancer (p>0.05). There is a necessity to conduct large-scale studies with adequate methodological quality and larger sample size in order to come to a definitive conclusion.

Influence of angiotensin converting enzyme (ACE) gene rs4362 polymorphism on the progression of kidney failure in patients with autosomal dominant polycystic kidney disease (ADPKD).

Background & objectives: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disorder, characterized by the fluid filled cysts in the kidneys leading to end stage renal failure in later years of life. Hypertension is one of the major factors independently contributing to the chronic kidney disease (CKD) progression. The renin-angiotensin aldosterone system (RAAS) genes have been extensively studied as hypertension candidate genes. The aim of the present study was to investigate the role of angiotensin converting enzyme tagging - single nucleotide polymorphisms (ACE tag-SNPs) in progression of CKD in patients with ADPKD. Methods: In the present study six ACE tagSNPs (angiotensin converting enzyme tag single nucleotide polymorphisms) and insertion/deletion (I/D) in 102 ADPKD patients and 106 control subjects were investigated. The tagSNPs were genotyped using FRET-based KASPar method and ACE ID by polymerase chain reaction (PCR) and electrophoresis. Genotypes and haplotypes were compared between ADPKD patients and controls. Univariate and multivariate logistic regression analyses were performed to assess the effect of genotypes and hypertension on CKD advancement. Mantel-Haenszel (M-H) stratified analysis was performed to study the relationship between different CKD stages and hypertension and their interaction. Results: All loci were polymorphic and except rs4293 SNP the remaining loci followed Hardy-Weinberg equilibrium. Distribution of ACE genotypes and haplotypes in controls and ADPKD patients was not significant. A significant linkage disequilibrium (LD) was observed between SNPs forming two LD blocks. The univariate analysis revealed that the age, hypertension, family history of diabetes and ACE rs4362 contributed to the advancement of CKD. Interpretation & conclusions: The results suggest that the ACE genotypes are effect modifiers of the relationship between hypertension and CKD advancement among the ADPKD patients.

The Correlation of ACE I/D Gene Polymorphisms with the Antihypertensive Efficacy of Irbesartan Among Hypertensive Patients / 昆明医科大学学报

Objective To analyze the correlationship of ACE I/D gene polymerphisms with the anti-hypertensive efficacy of irbesartan among essential hypertension (EH) patients in Yunnan han people.Methods One hundred EH patients hypertension were treated with irbesartan 150mg once daily for 4 weeks,and anti-hypertensive efficacy were monitored during the treatment.Results There was a significant difference between anti-hypertensive efficacy of irbesartan among different genotype groups,DD group ＞ID group ＞Ⅱ group (P ＜ 0.05) Conclusions There is different therapy responsiveness in diffenent genotypes.ACE I/D polymorphism may be an important hereditary factor that impacts the efficacy of irbesartan.

Prognostic Significance of ACE and PAI-1 Genes Polymorphisms with Diabetic Retinopathy and Diabetic Non-Retinopathy in Type 2 Diabetes.

Background: ACE a renin-angiotensin system that regulates blood pressure, balance of fluids and salts in body and PAI-1 is a serine protease inhibitor, which inhibits tissue plasminogen activator andurokinase.They are thought to play an important role in pathophysiology of kidney disease in diabetes. Aim: In our present study, we studied the association of altered ACE-gene and PAI-1 gene with diabetic retinopathy (DR) and NDR in 592 samples consisted of (cohort I; 196 DR patients, cohort II; 200 diabetic nonretinopathy (DNR) and cohort III, 196 respective controls. Methods: For genotyping of ACE-gene and PAI-1 gene, genomic DNA was isolated and purified which was then amplified by PCR, and thePCR products analyzedwere by Agarose gel electrophoresis. Results: In first part, the ACE genotype and allele frequency distribution was studied. For ACE gene polymorphism, the genotype and allele frequency distribution were analyzed in DR subjects and respective controls. The results indicated that there is no statistically significant difference between DR males and females compared to respective controls. The results were significantly high between genotype frequencies of DR and DNR in males. The recessive model was found to be significantly associated with the DR male subjects (OR=0.45 [95% CI=0.20-0.99], p<0.05), whereas in females these are non-significant as compared to respective controls individuals. In second part of study, the disease status analysis of ACE gene on basis of DR stages (NPDR and PDR) was observed. The χ2 analysis indicated that results are significantly different between NPDR and respective controls (χ2=8.75, p=0.01) .And in third part of present study, disease status analysis for PAI-1 gene on the basis of DR stages (NPDR and PDR) was studied, which indicated statistically nonsignificance. The χ2 analysis values for DNR and NPDR and for DNR and PDR was (χ2=0.48, p>0.05)(χ2 =2.00, p>0.05) respectively, Conclusion: Our present study suggests that changes in genetic polymorphisms of ACE-gene and PAI-1 gene in DR, DNR and T2D Patients are risk factors, which may serve as useful prognostic markers.

Association of Angiotensin Converting Enzyme I/D and alpha-actinin-3 R577X Genotypes with Growth Factors and Physical Fitness in Korean Children

This study analyzed the differences in aerobic and anaerobic exercise ability and growth-related indicators, depending on the polymorphism of the ACE and the ACTN3 genes, to understand the genetic influence of exercise ability in the growth process of children. The subjects of the study consisted of elementary school students (n=856, age 10.32+/-0.07 yr). The anthropometric parameters, physical fitness and growth factors were compared among groups of the ACE I/D or the ACTN3 R577X polymorphisms. There were no significant differences between the anthropometric parameters, physical fitness and growth factors for the ACE gene ID or the ACTN3 gene R577X polymorphism. However, the DD type of ACE gene was highest in the side step test (p<0.05), and the DD type was significantly higher than the II+ID type (p<0.05) in the early bone age. The combined group of the ACE gene II+ID and the ACTN3 gene XX type significantly showed lower early bone age (p< 0.05). This study did not find any individual or compounding effects of the polymorphism in the ACE I/D or the ACTN3 R577X polymorphisms on the anthropometric parameters, physical fitness and growth factors of Korean children. However, the exercise experience and the DD type of the ACE gene may affect the early maturity of the bones.

Angiotensin-converting enzyme inhibitors in the treatment of sarcoidosis and association with ACE gene polymorphism: Case series.

Angiotensin-converting enzyme (ACE) is used as a marker for sarcoid disease activity.1 We present an observational study of four African-American patients all of whom demonstrated improvement in their sarcoidosis after treatment with ACE inhibitors for hypertension.

Angiotensina-(1-9) disminuye el remodelamiento cardiovascular hipertensivo independiente de los niveles de ECA y de angiotensina II / Angiotensin-(1-) reduces hypertensive cardiovascular remodeling independent of ACE and Ang II levels

Resumen: La enzima convertidora de angiotensina I (ECA2) a través de Angiotensina (Ang)-(1-9) más que Ang-(1-7) contrarresta los efectos deletéreos de ECA y Ang II. Se desconoce si Ang-(1-9) es efectiva en el tratamiento del remodelamiento cardiovascular (RMCV) hipertensivo, en ratas con polimorfismo del gen de la ECA. Objetivo: Determinar el efecto de Ang-(1-9) en el tratamiento del RMCV hipertensivo en ratas con niveles genéticamente determinados de ECA y Ang II. Métodos: Ratas normotensas homocigotas, Lewis (LL) y Brown Norway (BN), se les indujo HTA a través del modelo Goldblatt (GB, 2 riñones-1 pinzado). Después de 4 semanas, las ratas hipertensas se rando-mizaron para recibir Ang-(1-9) (602 ng/Kg min) o una coadministración de Ang-(1-9)+A779 (100 ng/Kg min, antagonista del receptor MAS de Ang-(1-7)) durante 14 días mediante una minibomba. Como controles se usaron ratas sometidas a operación ficticia (Sham). Se determinó masa corporal (MC), presión arterial sistólica (PAS), masa ventricular (MV), área de cardiomiocitos (AC), área y grosor de la túnica media (ATM, GTM), fracción volumétrica de colágeno total (FVCT) en el ventrículo izquierdo (VI), niveles proteicos de colágeno tipo I (Col I) en la aorta (Ao) y la infiltración de macrófagos en Ao y VI, por medio de su molécula especifica ED1 (ED1-Ao, ED1-VI). Resultados: La administración de Ang-(1-9) disminuyó significativamente PAS, MV, AC, FVCT, Col I, ATM, GTM, ED1-Ao (-) y ED1-VI, en las ratas hipertensas LL y BN respecto a las ratas GB sin tratamiento, respectivamente. Este efecto no fue inhibido por el antagonista A779. El polimorfismo de la ECA no modificó la respuesta al tratamiento. Conclusión: Ang-(1-9) redujo eficazmente la HTA y el RMCV secundario, independiente al polimorfismo en el gen de la ECA. Este efecto posiblemente es directo ya que no fue mediado por Ang-(1-7). Fondecyt 1100874.

Background: The angiotensin I converting enzyme 2 (ACE2) counteracts the deleterious effects of ACE and Ang II through angiotensin (Ang) -(1-9) rather than Ang-(1-7). In addition, it is not clear whether Ang-(1-9) is effective in the reversal of hypertensive cardiovascular remodeling (CVRM) in rats with ACE gene polymorphism. Objective: To determine the effect of Ang-(1-9) in the prevention of hypertensive CVRM in rats with genetically determined levels of ACE and Ang II. Methods: In normotensive homozygous Lewis (LL) and Brown Norway (BN) rats hypertension was induced by the Goldblatt 2 kidney-1 pinch model. After 4 weeks, rats were randomized to receive Ang- (1-9) (602 ng / Kg min) or the co administration of Ang- (19) + A779 (100 ng / kg min, a MAS receptor antagonist of Ang- (1-7)) for 14 days. Sham operated rats were used as controls. We determined body mass (BM), systolic blood pressure (SBP), ventricular mass (VM), cardiomyocyte area (CA), area and thickness of the aortic media (ATM, TTM), LV total collagen volume fraction (FVCT), type I collagen protein levels (Col I) in the aorta (Ao) and macrophage infiltration in LV and Ao, through its specific molecule ED1 (ED1-Ao, ED1-VI). Results: Continuous administration of Ang- (1-9) significantly decreased SBP, VM, CA, TCVF, Col I, TTM, and ED1 in the aorta and left ventricle of hypertensive rats. This effect was not inhibited by the antagonist A779. ACE polymorphism did not modify the response to treatment. Conclusion: Ang- (1-9) effectively reduced hypertension induced CVRM independent of ACE gene polymorphism. This effect was not mediated by Ang- (1-7).

Angiotensin I-converting enzyme gene polymorphism and diabetic nephropathy in Filipino type 2 diabetes mellitus patients / Journal of the ASEAN Federation of Endocrine Societies

Objective. Previous studies have demonstrated the role of genetic susceptibility in the pathogenesis of diabetic nephropathy. The study aimed to determine the frequencies of angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in a pilot population of Filipino type 2 diabetic patients and normal controls. Methods. An analysis of the ACE gene polymorphism was performed in 42 diabetic patients with and without nephropathy, and 24 normal controls. The analysis was done using polymerase chain reaction, restriction enzyme digestion, and gel electrophoresis techniques to determine the polymorphism (II, DD or ID). Independent T-tests and chi-square tests were used to compare clinical characteristics, and logistic regression analysis was done to determine odds ratio for development of nephropathy. Results. The ID polymorphism of the ACE gene was more frequent (52.4%) in patients with diabetic nephropathy (n=21). In those without nephropathy (n=21), II was more common (61.9%). ID was the more frequent genotype in the normal controls (n=24) (58.3%). The odds of developing diabetic nephropathy were increased by 4.8 times in those with ID polymorphism, and 2.9 times in those with DD. Conclusion. The D allele was more common in patients with diabetic nephropathy, similar to the observation in South Indian patients. Since the study involved only a small pilot group, studies on a larger population is needed to establish the hypothesized role of the D allele in susceptibility to diabetic nephropathy in Filipinos.

Association between ACE gene polymorphism and type 2 diabetic nephropathy / 吉林大学学报(医学版)

0.05).Conclusion There is no significant correlation between ACE gene polymorphism and type 2 diabetic nephropathy.

Polymorphism of the ACE Gene in Dialysis Patients: Overexpression of DD Genotype in Type 2 Diabetic End-Stage Renal Failure Patients

The angiotensin-converting enzyme (ACE) gene DD homozygote has been suggested to be a significant risk factor for the progression of diabetic nephropathy. We analyzed clinical parameters and ACE genotype distribution between type 2 diabetic patients at the extremes of renal risk, i.e. an end-stage renal failure (ESRF) group (n = 103, group 1) who were on dialysis therapy due to progression of diabetic nephropathy, and a no progression group (n = 88, group 2) who had maintained normal renal function and normoalbuminuria for more than 15 years. There were no significant differences in age, sex, body mass index, HbA1c level, or lipid profiles between the two groups (p > 0.05). Group 1 had a significantly higher prevalence of hypertension [group 1: 82.5% (85/103) vs. group 2: 50.0% (44/88), p < 0.05] and diabetic retinopathy [group 1: 103/103 (100%) vs. group 2: 28/88 (31.8%), p < 0.05] than group 2. Daily urinary albumin excretion was also higher in group 1 than in group 2 [group 1: 2873 +/- 2176 mg/day vs. 12 +/- 7 g/day, p < 0.05]. The frequencies of the DD, ID, and II genotypes of the ACE gene in group 1 and group 2 were 26.2%, 47.6%, and 26.2%, and 7.9%, 57.9%, and 34.2%, respectively. The ACE genotype frequencies between the two groups were significantly different according to a chi-square test with Bonferroni's correction (p = 0.004). The presence of the DD genotype increased the risk of ESRF 4.286-fold compared to the II genotype [odds ratio 4.286, 95% CI 1.60- 11.42, p = 0.005]. The frequency of the D-allele was higher in both male and female patients in group 1 compared to group 2, but reached statistical significance only in males [male, group 1: 50.8% vs. group 2: 35.0%, p = 0.018, female, group 1: 48.8% vs. group 2: 39.5%, p = 0.231]. This study, although limited by sample size, showed that type 2 diabetic ESRF patients more frequently expressed the DD genotype. These findings may substantiate the previously noted relationship between the ACE DD genotype and the progression of diabetic nephropathy in Korean type 2 diabetic patients.

Apolipoprotein E and ACE genetic polymorphism and nephropathy in type 2 diabetic patients / 대한내과학회지

BACKGROUND: The aim of this study was to investigate the association between apo E and ACE genetic polymorphism and diabetic nephropathy. METHODS: One hundred eighteen patients with type 2 diabetes who had a duration of diabetes longer than 8 years were divided into the three apo E groups (E2, E3, E4) and three ACE groups (II, ID, DD). Plasma levels of lipids were measured. The frequency of diabetic nephropathy and clinical and biochemical characteristics were compared among the Apo E and ACE genotype groups. RESULTS: The frequency of overt nephropathy was significantly greater in apo E2 patients with diabetes (46.7%) than apo E3 (16.7%) or apo E4 patients (10.5%). Logistical regression analysis showed that odds ratio of apo E2 and apo E4 genotypes for the presence of overt nephropathy were 4.779 (p<0.01) and 0.643 (p=0.583), respectively. Plasma TG levels were significantly greater in apo E2 patients. This study did not show an association between ACE gene polymorphism and diabetic nephropathy, and no interaction between Apo E and ACE gene polymorphism. CONCLUSION: Apo E2 is a prognostic risk factor for diabetic nephropathy in Korean type 2 diabetes. TG may have an important role of diabetic nephropathy. There were not synergistic effect between Apo E and ACE gene polymorphism in diabetic nephropathy.

Genetic and Environmental Factors that Influence on Erythropoietin Resistance in Patients on Hemodialysis / 대한신장학회잡지

BACKGROUND: Erythropoietin (EPO) requirement to reach a specified target hemoglobin level varies in patients on dialysis, the reasons being multifactorial. Angiotensin II has been shown to stimulate proliferation of early erythroid progenitors via erythropoietin and the plasma level of angiotensin II has been strongly associated with angiotensin converting enzyme (ACE) gene polymorphism. EPO resistance index (ERI, weekly rhEPO dose/hematocrit/body weight) is a collective responsiveness between EPO and hematocrit. We have evaluated whether ACE gene polymorphism might exert effect on ERI and also have analysed various laboratory parameters that could affect erythropoietin requirement in HD patients. METHODS: We have compared various demographic data and laboratory parameters, including age, sex, months on dialysis, body mass index (BMI), EPO requirement, ERI, high sensitivity C-reactive protein (hsCRP), ferritin, albumin, hematocrit, iPTH, Kt/V, normalized protein catabolic rate (nPCR), cause of renal failure and whether or not patients were on ACE inhibitor or Angiotensin receptor blocker (ARB), in 199 patients on hemodialysis therapy [M: F 94: 105, Age 61+/-13, duration of dialysis 63 (3-287 months)] according to ACE gene polymorphism (II, ID, DD). We also have assessed independent association of ERI with demographic variables and laboratory parameters using linear regression analysis. RESULTS: There was statistically significant difference (p=0.034) in ERI in the II/ID group compared to the DD group and it was lower in the DD group. But there was no statistically significant difference in other demographic data and laboratory parameters according to ACE gene polymorphism. In the linear regression analysis, lower BMI (p<0.001), female gender (p=0.001), and ACE gene polymorphism (non-DD vs. DD, p=0.027) were determined to be independent factors affecting high ERI. CONCLUSION: ACE gene polymorphism could be determining factor of EPO requirement in patients on hemodialysis. Improving nutritional status might be helpful in reducing EPO requirement and we should consider the gender difference in determining EPO dose in patients on hemodialysis.

Risk Factors for Atrophic Renal Scar

PURPOSE: An atrophic renal scar(RS) is one of the underlying causes for childhood hypertension and chronic renal failure. The risk factors for atrophic renal scar were evaluated. METHODS: 41 children, who presented with first febrile urinary tract infection at the Ewha Womans University Hospital between 1995 and 2003 and had generalized atrophic RS on 99mTc-DMSA renal scan, were retrospectively studied. Atrophic RS was divided into severe atrophic RS(n=14) if relative uptake on renal scan was below 10%, or mild atrophic RS(n= 27) if relative uptake on renal scan was between 10-35%. RS was defined as congenital if the scar was detected on the first renal scan, and as acquired if the scar developed on the follow-up renal scan from acute pyelonephritis of the first renal scan. The control group was consisted of randomly selected 41 children with segmental RS. The risk factors for atrophic RS such as the generation time, VUR, gender and ACE gene polymorphism were evaluated. RESULTS: The age distribution of atrophic RS and segmental RS did not differ significantly (P>0.05). The rate of congenital RS in atrophic RS was 61.0%(25/41), which was significantly higher than 9.8%(4/41) of segmental RS(P0.05). But in children with VUR, there was a higher proportion of males with severe atrophic RS than segmental RS(85.7%:45.5%). ACE gene polymorphism did not differ between the atrophic and segmental RS groups, irrespective of the presence of VUR(P>0.05). CONCLUSION: Most atrophic RSs were congenital which could not be preventable postnatally and the major risk factors were VUR and the male gender. ACE gene polymorphism was not the significant risk factor for an atrophic RS.

Angiotensin Converting Enzyme Gene Polymorphism in Alport Syndrome

PURPOSE: Alport syndrome is clinically characterized by hereditary progressive nephritis causing ESRD with irregular thickening of the GBM and sensory neural hearing loss. The mutations of type IV collagen gene(COL4A5) located on the long arm of X chromosome is considered responsible for most of the structural abnormalities in the GBM of Alport patients. Since no definite clinical prognostic predictor has been reported in the disease yet, we designed this study to evaluate the significance of genetic polymorphism of the angiotensin converting enzyme in children with Alport syndrome as a prognostic factor for disease progression. METHODS: ACE I/D genotype were examined by PCR amplification of the genomic DNA in 12 patients with Alport syndrome and 12 of their family members. Alport patients were divided into two groups; the conservative group, those who had preserved renal function for more than 10 years of age, the early CRF group, those who had progressed to CRF within 10 years of age. RESULTS: The mean age of onset was 3.45+/-2.4 years in the conservative group, 4.4+/-1.2 years in the early CRF group. Sex ratios were 5:3 and 2:1 in each group. Among 12 cases of patients, 4 cases were in early CRF group and their mean duration of onset to CRF was 4.5 years(8.9 years of age). Eight patients(67%) were in the conservative group and they had normal renal function for more than 10 years of age(mean duration of renal preservation was 10.6 years). The incidence of II type ACE gene were in 25.0%(3 cases), ID type in 41.7 %(5 cases), DD type in 33.3%(4 cases). There was no significant difference between Alport patient and normal control(II type 44.3%, ID type 40.9%, DD type 14.8%). The incidence of DD type of early CRF group were higher than that of the conservative group(75% vs 12.5 %)(p<0.05). There was no difference in ACE gene polymorphism between normal Alport family members and control group. CONCLUSION: Even though there was no significant difference of ACE polymorphism between Alport patients and the normal control group, the incidence of DD type is significantly increased in early CRF group which means DD type of ACE polymorphism has a possibility of being a predictor for early progression to CRF in Alport patients.

Angiotensin Converting Enzyme Gene Insertion/Deletion Polymorphism and E-selectin S128R Polymorphism in Peripheral Atherosclerotic Occlusive Disease

PURPOSE: Studies concerning the relationship between gene polymorphisms and potentially implicated cardiovascular disease have produced conflicting findings, in part due to differences in ethnic background between populations. These led us to evaluate the impact of polymorphisms in the ACE and E-selectin genes on peripheral artery atherosclerosis in a Korean population. METHODS: We studied 92 male patients (median age: 65.9, range: 48~82) with severe peripheral atherosclerosis documented by angiography and ABI (ankle brachial index). The control group comprised 290 healthy persons (male 216, female 64, median age 61.3, range 20~90) without symptoms for peripheral vascular disease. The blood samples were stored at -20oC until DNA was ready to be extracted. The inorganic procedure for DNA extraction was based on the method described by Miller et al. The ACE and E-selectin polymorphisms were detected by polymerase chain reaction (PCR) amplification. RESULTS: The distribution of ACE genotypes of the patient group was as follows: II, 34 (37.0%); ID, 46 (50.0%); and DD, 12 (13.0%). It was not significantly different from that of the control subjects: II, 104 (37.1%); ID, 133 (47.6%); and DD, 43 (15.3%) (P=0.80). The allele frequencies of the patient group were as follows: I, 114 (62.0%); and D, 70 (38.0%). It was not significantly different from that of the control subjects: I, 341 (60.9%); and D, 219 (39.1%) (P= 0.80). The frequencies of E-selectin genotypes in the patient group were as follows: Ser/Ser 85 (93.4%); Ser/Arg, 6 (6.6); and Arg/Arg, 0 (0%). It was not significantly different from that of the control subjects: Ser/Ser, 262 (93.6%); Ser/Arg, 18 (6.4%); and Arg/Arg, 0 (0%) (P=0.95). In addition, the allele frequencies of the patient group were as follows: Ser, 176 (96.7%); and Arg, 6 (3.3%). It was not significantly different from that of the control subjects: Ser, 542 (96.8%); and Arg 18 (3.2%) (P=0.95). CONCLUSION: The I/D polymorphism of the ACE gene and E-selectin S128R polymorphism were not significantly different between the atherosclerotic patient group and the normal control group in Koreans.

ACE gene polymorphism and renal responsiveness to ACE inhibitors in IgA nephropathy patients

We examined the renal responsiveness to ACE inhibitor in IgA nephropathy (IgAN) patients according to the grouping of ACE gene polymorphism. Sixty one patients diagnosed as IgAN by renal biopsy and prescribed with ACE inhibitors were enrolled. Genomic DNA was extracted from whole blood and PCR was performed. The I/D polymorphism was determined by the presence of the 287 bp fragment in intron 16 of chromosome 17. During the follow-up period (mean+ADs- 44.6 months, median: 44.5 months, 5 to 113 months), the blood pressure of 61 patients was controlled below 130/80 mmHg. The renal responsiveness was determined by the degree of changes of proteinuria at 12 months after initiation of ACE inhibitors and by the slope of reciprocal variation of the serum creatinine against follow-up duration ?(1/Cr2-1/Cr1)/durations?. The distribution of the II, ID and DD genotype among 61 patients was 21, 16 and 24 patients, respectively. There were no differences among three genotypes in age, sex, the number of patients with initial blood pressure over 140/90 mmHg, initial serum creatinine level, the number of patients with initial azotemia (+AD4- 1.4 mg/dL) and with initial 24-hr proteinuria amount over 2.0 g. Significant anti-proteinuric effect of ACE inhibitor was found in IgAN (p +AD0- 0.001), but no significant difference was found among genotypes. Significant difference (p +AD0- 0.011) was noticed between II type and DD type in the slope of reciprocal variation of the serum creatinine against follow-up duration. In conclusion, efficacy of ACE inhibitors on renal function preservation in IgAN was more pronounced in DD genotype than II genotype.

Polymorphism of angiotensin I converting enzyme (ACE) gene according to the severity of asthma in Korean adult asthmatics / 천식및알레르기

BACKGROUND AND OBJECTIVE: Many chemical mediators such as histamine, prostaglandins, leukotrienes, bradykinin, angiotensisn II (A II), and even angiotensin converting enzyme (ACE) affect the pathophysiology of asthma. ACE exists in the epithelium, endothelium, neuroepithelium, plasma, and especially in high concentrations in human lung tissue. ACE converts A I to A II, which is highly vasoconstrictive, bronchoconstrictive, inflammatory substance, and can also inactivate bradykinin. ACE polymorphism determines the level of ACE such as DD, higher concentration of ACE, but II, lowest concentration of that, so in DD type, the level of A II increase, but that of bradykinin decrease. From that point we can speculate polymorphism of ACE gene anyhow affects asthma, so we carried out this study for evaluating relationships between the ACE genotype distribution and genesis and severity of asthma in Korean adult asthmatics. MATERIALS AND METHODS: The study population consisted of 150 asthmatics, 57 patients of non asthmatic lung diseases including lung cancer (n=10), pulmonary tuberculosis (n=27), empyema (n=3), pneumonia (n=11), bronchiectasis (n=5) and lung abscess (n=1) and 100 normal healthy subjects without hypertension, cardiovascular disease, diabetes mellitus and nephropathy which may bias the result. Bronchial asthmatics were classified into 3 groups according to the criteria of the NAPE. PCR (polymerase chain reaction) for ACE genotypes was performed. PCR products were electrophoresed in 1% agarose gels, and then DNA pattern was directly visualized under ethidium bromide staining. RESULTS: The frequency for II, ID, and DD genotypes were 46 (46%), 38 (38%), 16 (16%) in control group, 59 (39.6%), 74 (49.5%), 17 (10.9%) in asthma group and 28 (49.1%), 24 (42.1%), 5 (8.8%) in non-bronchial lung disease group, respectively. There was no signi- ficant difference in frequency of ACE genotype distribution among the 3 groups (p > 0.05). The frequency for II, ID, and DD genotypes in the 3 groups of asthmatics were 17 (34%), 27 (54%), 6 (12%) in mild subset, 13 (26%), 30 (60%), 7 (14%) in moderate subset, and 11 (22%), 33 (66%), 6 (12%) in severe subset. Even though there was also no significant difference among the 3 severity subsets in the asthma group, the frequency of non-DD subsets such as II and ID was higher in moderate and severe asthmatics. CONCLUSION: The results suggest that ACE gene polymorphism dose not affect the genesis but can progress asthma in Korean adult asthmatics. However, further mass studies on asthmatics will be needed to clarify the effect of ACE polymorphism on the severity of Korean adult asthmatics.

Correlation Between Angiotensin-Converting Enzyme(ACE) Inhibitor Induced Dry Cough and ACE Gene Insertion/Deletion(I/D) Polymorphism / 결핵

BACKGROUND: Persistent nonproductive cough is a major adverse effect encountered with ACE inhibitor treatment and the most frequent reason for withdrawal of the drug. The mechanism of cough was postulated to be associated with accumulation of bronchial irritants which are substrates of ACE. It has been speculated that occurrence of this adverse effect is genetically predetermined; in particular, variants of the genes encoding ACE. To investigate this relationship, we determined ACE gene Insertion/Deletion polymorphism in subjects with and without a history of ACE inhibitor-induced cough. METHODS: Among the 339 patients with ACE inhibitor treatment, subjects who developed cough that resolved when not taking medication were designated to cough group and other subjects who did not complain cough were designated to non-cough group. Clinical characteristics of the patients were collected by review of medical records. ACE genotypes were determined by PCR amplification of DNA from peripheral blood RESULTS: 37 patients complained of dry cough(cough group) and 302 patients did not complained of cough(non-cough group). The incidence of ACE inhibitor induced dry cough was 10.9%. There was a preponderance of females in the cough group (M:F=24.3%:75.7%) compared to the non-cough group(M:F=49.7%:50.3%, p=0.004). There was no significant difference in mean age, underlying diseases, and kinds and frequencies of ACE inhibitors and their mean dosage between the both groups. ACE genotypic frequencies were I/I : I/D : D/D = 16.2%:18.9%:64.9% in the cough group and 18.9%:18.2%:62.9% in the non-cough group which showed no significant difference between the both groups(p=0.926). Allelic frequencies were I : D = 25.7%:74.3% and 28.0%:72.0% in the cough and non-cough group respectively and the difference was not significant(p=0.676). CONCLUSION: The incidence of ACE inhibitor-induced cough are 10.9%, and women are more susceptible to ACE inhibitor-induce cough. ACE inhibitor induce dry cough is not associated with ACE gene Insertion/Deletion polymorphism.

Relationships between Angiotensin - Converting Enzyme Gene Polymorphism and Initiation and Progression of Renal Failure in Patients with Non-Insulin Dependent Diabetes Mellitus / 대한내과학회지

OBJECTIVE: Diabetic nephropathy is an important cause of end-stage renal disease and associated with morbidity and mortality of the patients with diabetes mellitus. It has been reported that the genetic susceptibility may be an important factor in the development of nephropathy in diabetic patients, but the genes responsible for the predisposition to diabetic nephropathy are not known. The genes of the renin-angiotensin systems are plausible candidate genes and the genetic polymorphism of angiotensin-converting enzyme(ACE) gene has been extensively studied for its possible role. Recently, the association of the ACE gene polymorphism with nephropathy as well as myocardial infartion was reported in diabetic patients. To elucidate the contribution of ACE gene polymorphism to the initiation and progression of diabetic nephropathy, we typed the alleles of the ACE gene in 139 patients with non-insulin dependent diabetes mellitus (NIDDM). METHODS: After the extraction of genomic DNA from peripheral blood leukocytes, PCRs were performed using the flanking and insertion specific primers, respectively. The PCR products were electrophoresed in 1.5% agarose gels, and DNA was visualized directly with ethidium bromide staining. RESULTS: Subjects were consisted of 139 patients with diabetes mellitus and male to female ratio was 63:76, mean age 55.8+/-12.0 years, mean duration of diabetes 9.5+/-7.8 years. ACE genotypes in whole population were 37.4% DD genotype, 51.1% ID genotype and 11.5% II genotype. The ACE genotype distributions, age, sex, blood pressure and body mass index were not different in diabetic subjects with or without nephropathy. No significant differences on the clinical parameters such as age, sex, blood pressure, body mass index, duration of diabetes, incidence of hypertension, cardiovascular complication, diabetic neuropathy and retinopathy, serum creatinine and 24hour albumin excretion were noted according to the ACE genotypes. Forty-six patients with NIDDM were followed over 3 years. The mean follow-up duration was 6.4+/-2.7 years, mean age was 54.4+/-10.2 years, and mean duration of diabetes was 14.7+/-6.1 years. ACE genotypes were 36.9% DD genotype, 52.2% ID genotype and 10.9% II genotype. The ACE genotype distributions were not different in the patients among DD, II or II genotypes. There were also no significant differences in terms of age, sex, duration of diabetes, blood pressure, body mass index, prevalence of hypertension, cardiovascular complication, diabetic neuropathy and diabetic retinopathy. But the rate of decline of creatinine clearance(deltacreatinine clearance, ml/min/year) was higher in DD genotype than ID or II genotypes(3.3+/-7.2 vs 2.8+/-6.2 vs 2.7+/-9.8), and the rate of change of 24-hour protein excretion(deltaurinary protein excretion, mg/24hours/year) was higher in DD genotype than ID or II genotypes(89.3+/-220.0 vs 74.1+/-156.8 vs 70.9+/-546.3). But they did not reach to statistical significance. CONCLUSION: We found that insertion/deletion polymorphism of ACE gene is not implicated in the initiation of diabetic nephropathy of Korean NIDDM patients, but also found the possibility that progression of diabetic nephropathy may be associated with it. We need large scaled prospective follow-up studies on the effects of ACE polymorphism in the progression of diabetic nephropathy.