Angiotensin I-converting Enzyme Polymorphism Research Articles

Abstract 5592: Lack of association between AGTR1 (A168G and T825A) and ACE T5529C polymorphisms with breast cancer among Brazilian women

Abstract Background: Angiotensin II (AngII) exerts promitotic, pro-proliferative and angiogenic effects and the administration of angiotensin I-converting enzyme (ACE) inhibitors reduces tumor growth in animal models of cancer. AngII type 1 receptor (AGTR1) is found in a wide variety of normal tissues, increased expression is often found in the corresponding neoplastic tissues, suggesting that its overexpression is involved in carcinogenesis. In a previous study we observed that the ID genotype might be protective against breast cancer and also that the ACE (I/D) polymorphism is a possible target for developing genetic markers for breast cancer. Other authors have also observed the association of the ACE with breast cancer risk. To further test the hypothesis that AngII participates in breast carcinogenesis through AGTR1 and ACE, we examined genetic polymorphisms in the 5’-region of the AGTR1 gene (A-168G and T-825A) and in the ACE (T5529C) in relation to risk of breast cancer among Brazilian women. Methods: Genotyping was performed through Real Time PCR (A168G and T825A) or PCR-RFLP (T5529C) using genomic DNA extracted from buccal cells of subjects with or without breast cancer.Results: Patients with (case) or without (control) breast cancer aging from 30 to 90 years old were genotyped for A168G (n=516), and the following frequencies obtained for AA, AG and GG in % were, among cases: 63, 30, 07 and among controls: 64, 32, 04 (p = 0.89). For T825A (n=562), we determined the frequency of TT, TA and AA (in %, cases: 62, 33, 05; controls: 59, 33, 08; p = 0.68). At last, for ACE (T5529C) (n=272) these are the obtained frequencies for TT, TC and CC genotypes in %, among cases: 65, 23, 12 and among controls: 55, 29, 15 (p = 0.39). Conclusion: Our results suggest a lack of significant association between AGTR1 polymorphisms (A168G and T825A) with breast cancer risk in the Brazilian population, in contrast to a previous result among Chinese women, where an association of the AGTR1 polymorphisms with breast cancer has been reported. Regarding the ACE T5529C polymorphism, it also did not show any association with breast cancer risk in the present study, differently from the observed for another polymorphism of the same gene, the ACE (I/D). Therefore, the AGTR1 (A168G and T825A) and ACE (T5529C) variant genotypes do not appear to be related to risk of breast cancer among Brazilian women. Support: FAPESP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5592. doi:10.1158/1538-7445.AM2011-5592

Association of angiotensin I converting enzyme (insertion/deletion) and angiotensin II type 1 receptor (A1166C) polymorphisms with breast cancer prognostic factors in iranian population

It has been indicated that renin-angiotensin system (RAS) has role in various steps of cancer progression. The presence of RAS components has been shown in normal and breast cancer tissue. insertion/deletion (I/D) is one of angiotensin I converting enzyme (ACE) polymorphisms and A1166C is one of angiotensin II type-1 receptor (AT1R) polymorphisms which have been associated with various diseases such as cardiovascular diseases. In the present study, we aimed to substantiate the putative significance of ACE and AT1R on breast cancer biology by investigating the influence of their gene polymorphisms on breast cancer progression. The I/D and A1166C polymorphisms were evaluated by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), respectively in 70 breast cancer patients diagnosed with invasive breast cancer and 70 healthy women. Breast cancer prognostic factors were obtained from medical and pathology reports of patients. There was no significant difference between cases and controls for ACE (I/D) (P = 0.15) and AT1R (A1166C) genotypes (P = 0.86). In breast cancer patients, when DD genotype was used as reference group, the combination of II and ID genotypes was associated with increased HER-2 expression (P = 0.020; OR, 4.58; 95% CI, 1.26-16.60). Also, when AA genotype was used as reference group, the AC genotype was associated with higher tumor TNM stage (P = 0.024; OR, 4.66; 95% CI, 1.18-18.35). This is the first study indicating that ACE (I/D) polymorphism is associated with HER-2 expression and AT1R (A1166C) polymorphism is associated with tumor TNM stage in breast cancer patients.

Angiotensin I-Converting Enzyme Insertion/Deletion Polymorphism and Increased Risk of Gall Bladder Cancer in Women

Gall bladder cancer (GBC) is a relatively rare but highly fatal disease, particularly in North India. The angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism influences serum angiotensin II action, which has been associated with various malignancies. This population-based case-control study was undertaken to examine the potential association of ACE I/D variation with GBC in a North Indian population. Genotypes and allelic frequencies of the ACE I/D polymorphism (rs4646994) were determined for 233 GBC patients and 260 cancer-free controls randomly selected from the population using polymerase chain reaction. Odds ratio (OR) and 95% confidence interval were calculated in multivariate logistic regression analysis for the association of ACE polymorphism with GBC. The ACE I/D polymorphism was found to be nonsignificantly associated with an overall increased risk of GBC (OR = 1.04 and 1.38 for I/D and D/D genotypes, respectively; p(trend) = 0.375). The increased risk was predominant significantly in female cohort and nonsignificantly in GBC patients with gallstone status (OR = 1.63; p = 0.039 and OR = 1.37; p = 0.187, respectively). In summary, ACE I/D polymorphism may alter the susceptibility to GBC, especially in women.

Plasma Kallikrein and Angiotensin I-converting enzyme N- and C-terminal domain activities are modulated by the insertion/deletion polymorphism

Angiotensin I-converting enzyme (ACE) is recognized as one of the main effector molecules involved in blood pressure regulation. In the last few years some polymorphisms of ACE such as the insertion/deletion (I/D) polymorphism have been described, but their physiologic relevance is poorly understood. In addition, few studies investigated if the specific activity of ACE domain is related to the I/D polymorphism and if it can affect other systems. The aim of this study was to establish a biochemical and functional characterization of the I/D polymorphism and correlate this with the corresponding ACE activity. For this purpose, 119 male brazilian army recruits were genotyped and their ACE plasma activities evaluated from the C- and N-terminal catalytic domains using fluorescence resonance energy transfer (FRET) peptides, specific for the C-domain (Abz-LFK(Dnp)OH), N-domain (Abz-SDK(Dnp)P-OH) and both C- and N-domains (Abz-FRK(Dnp)P-OH). Plasma kallikrein activity was measured using Z-Phe-Arg-AMC as substrate and inhibited by selective plasma kallikrein inhibitor (PKSI). Some physiological parameters previously described related to the I/D polymorphism such as handgrip strength, blood pressure, heart rate and BMI were also evaluated. The genotype distribution was II n=27, ID n=64 and DD n=28. Total plasma ACE activity of both domains in II individuals was significantly lower in comparison to ID and DD. This pattern was also observed for C- and N-domain activities. Difference between ID and DD subjects was observed only with the N-domain specific substrate. Blood pressure, heart rate, handgrip strength and BMI were similar among the genotypes. This polymorphism also affected the plasma kallikrein activity and DD group presents high activity level. Thus, our data demonstrate that the I/D ACE polymorphism affects differently both ACE domains without effects on handgrip strength. Moreover, this polymorphism influences the kallikrein-kinin system of normotensive individuals.

No Evidence for Association Between the Renin-Angiotensin-Aldosterone System and Otosclerosis in a Large Belgian-Dutch Population

Otosclerosis is a frequent cause of hearing impairment in the Caucasian population and is characterized by abnormal bone remodeling of the otic capsule. Associations with several genes have been reported, and recently, an association between the renin-angiotensin-aldosterone system and otosclerosis has been suggested. Polymorphisms in 3 genes were investigated: angiotensinogen (AGT), angiotensin I-converting enzyme (ACE), and angiotensin II receptor, type 1. The polymorphisms in AGT and ACE were associated with disease, and both were reported to interact with each other. In the current study, a replication study was done in a large Belgian-Dutch population to investigate whether this association could be replicated. The same 3 polymorphisms in AGT, ACE, and angiotensin II receptor, type 1 as analyzed in the original study were investigated in 692 otosclerosis patients and 692 controls of Belgian-Dutch origin. None of the polymorphisms were significantly associated with disease. Interaction between AGT and ACE polymorphisms was not significant either. We could not confirm the association between AGT and ACE, nor could we find evidence for interaction between both genes in otosclerosis. Because the current patient set is much larger than the one from the original study, this study holds sufficient power to detect the previously reported associations. Nonreplication in this case probably indicates that the initial results were false positive, although a role for these genes in otosclerosis cannot be definitively ruled out.

Angiotensin-I Converting Enzyme Genotype Does Not Strongly Correlate With Elite Endurance Athlete Status In Ethiopians

There has been considerable interest over recent years in the use of the Angiotensin-I Converting Enzyme (ACE) gene as a marker of athletic performance. A previous study found no difference in ACE polymorphism between elite Kenyan endurance runners and demographically-matched controls (Scott et al. Comp Biochem Physiol A Mol Integr Physiol 141(2):169-175, 2005), a result that was somewhat surprising in view of contrasting findings in Caucasian populations. PURPOSE: To investigate the association between ACE polymorphisms and elite endurance athlete status in Ethiopians. METHODS: DNA was extracted from buccal swabs collected from 114 members of the Ethiopian national athletics team (E), 315 individuals representative of the general Ethiopian population (C), and 93 individuals from the Arsi region (A), where the majority of elite Ethiopian distance runners originate. RESULTS: There were no significant deviations from Hardy-Weinberg equilibrium in athletes or controls. Ethiopian athletes did not differ significantly from general controls (P = 0.076) or Arsi (P = 0.87) in their ACE ID genotype frequencies (E: 16% II, C: 8% II, A: 13% II). The tendency towards significance in ID genotype frequency between athletes and general controls was not replicated in ACE 22982 genotype (E: 13% AA, C: 12% AA, A: 13% AA), where no significant differences were found (E vs C: P = 0.95, E vs A: P = 0.73). CONCLUSIONS: As previously shown in elite Kenyan athletes, the ACE genotype is not directly associated with elite endurance status in Ethiopians. The tendency towards significance in ID genotype frequency between athletes and general controls may be a reflection of the region of Arsi where the majority of Ethiopian athletes originate. Research part-funded by The Royal Society, The Carnegie Trust for the Universities of Scotland, and The Wellcome Trust

Angiotensin-converting enzyme gene polymorphism in hypertensive rural population of Haryana, India.

Background:Essential hypertension is a complex genetic disorder influenced by diverse environmental factors. Of the various physiological pathways affecting the homeostasis of blood pressure, the renin-angiotensin system (RAS) is known to play a critical role. Angiotensin-I converting enzyme (ACE) is a significant component of RAS and an insertion/deletion (I/D) polymorphism in its gene has been implicated in predisposition to hypertension.Objective:The present study is aimed to determine the association, if any, of ACE I/D polymorphism with essential hypertension in a rural population of Haryana, India.Materials and Methods:The blood samples were collected from the patients visiting M. M. Institute of Medical Sciences, Mullana, Haryana. DNA from the patients (106) and control (110) specimens were isolated, amplified by PCR and analyzed employing agarose gel electrophoresis.Results:There was no significant difference in the distribution of DD, II and I/D genotypes of ACE polymorphism in essential hypertensive patients (28.8, 25.5, and 46.2%) and their ethnically matched normal control (24.5, 30, and 45.5), respectively. The two groups also presented with very similar allelic frequencies and were also found to be in Hardy-Weinberg equilibrium.Conclusions:The present study demonstrates that ACE I/D polymorphism is not a risk factor for essential hypertension in the hitherto unstudied rural population of Haryana.

Combined “pro-atherosclerotic” variants of the ACE and APOE genes increase the risk of the coronary artery disease associated with the presence of cigarette smoking

Objective — Cigarette smoking increases the synthesis of angiotensin-I converting enzyme (ACE) and induces oxidative modifications of the apolipoprotein E (apo E).Thus we explored the gene-environment interactions between APOE gene epsilon and ACE gene insertion/deletion polymorphisms and cigarette smoking in coronary artery disease (CAD) patients.Methods — We analysed 360 subjects: 171 CAD patients and 189 blood donors without a history of cardiovascular diseases. ACE and APOE polymorphisms were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods, respectively.To determine gene-environment interactions, epidemiological methodology was used.Results — The ACEDD genotype was a rather weak risk factor of CAD in the analysed population (OR = 1.87, P= 0.01).The differences in allele and genotype distribution of the APOE polymorphism were not statistically significant.The carriers of the combined genotype ACEDD + APOEɛ4ɛ4,ɛ3ɛ4,ɛ2ɛ4 were more frequent in patients, however, the differences were on the bound of statistical significance (P= 0.08). Logistic regression analysis showed that the ACEDD + apo Eɛ4ɛ4,ɛ3ɛ4,ɛ2ɛ4 cigarette smokers were much more frequent in the CAD group (OR = 11.68, 95%CI; 1.52-246.43, P= 0.009).We confirmed these results using the 4 ≈ 2 table approach and we found a synergistic effect of the ACEDD + APOEɛ4ɛ4,ɛ3ɛ4,ɛ2ɛ4 combined genotype and cigarette smoking (SI = 10.52, SIM = 6.09).Conclusions — We demonstrated the existence of the synergistic effect between cigarette smoking and the contemporaneous carrier-state of APOE e4 and ACED alleles which increased the risk of CAD to a large extent.

Lack of association of angiotensin I-converting enzyme gene polymorphism and premature myocardial infarction in Mauritian Indians

Eighty-five young Mauritian Indians, male survivors of premature myocardial infarction (MI) and thus belonging to a high risk group, were compared with 108 stringently selected controls for a possible association between premature MI and an insertion/deletion (I/D) polymorphism in the gene encoding angiotensin I-converting enzyme (ACE). The frequency of the D allele was 0.42 in the MI group and 0.43 in the control group, and thus no association between I/D polymorphism of ACE with susceptibility to early-onset MI was found in this population group. Other gene components of the renin-angiotensin system and lipid metabolism need to be explored to understand the genetic factors involved in causing MI at an early age.

Influence of angiotensin I‐converting enzyme polymorphism on development of post‐transplant erythrocytosis in renal graft recipients

Post-transplant erythrocytosis (PTE) is estimated at 5-20%. Angiotensin II generated by angiotensin I-converting enzyme (ACE) stimulates erythropoiesis. The highest activity of ACE is observed in DD genotype. The question arises if ACE gene polymorphism influences PTE. One-year prospective study included 89 kidney recipients (28 women and 61 men). Thirty-four (38%) recipients proved to be DD genotype, 36 (40%) ID, and 19 (22%) II genotype. Absolute PTE [hematocrit level (HCT) >50% and RBC > 5.5 mln/mm(3)] was found in 14 (19%) patients. PTE developed 6-12 months after kidney Tx. There were no significant differences in genotype distribution between patients with and without PTE. ANOVA showed that the most significant predictor of PTE development was the time since kidney Tx (p < 0.0001). Analysis of logistic regression showed that male sex was the most important factor in PTE development 12 months after kidney Tx (OR = 13.6: 95% CI 1.2-150.9, p < 0.05). D allele increased the PTE risk (OR = 3.3 for each allele: 95% CI 1.1-10.4, p < 0.05), the use of angiotensin-converting enzyme inhibitors (ACEI) decreased the PTE risk (OR = 0.15: 95% CI 0.03-0.85, p < 0.05). In patients with DD genotype, there was a correlation between hemoglobin, RBC and HCT concentration, 12 months after Tx and panel of reactive antibody value before Tx (Rs = +0.43, p < 0.05). Male sex and D allele presence increase the risk of PTE development, especially in highly immunized patients. The use of ACEI decreases the risk of PTE development.

Reduced plasma levels of angiotensin-(1-7) and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

The relationship between preeclampsia and the renin-angiotensin system (RAS) is poorly understood. Angiotensin I-converting enzyme (ACE) is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II) and inactivating the vasodilator angiotensin-(1-7) (Ang-(1-7)). ACE (I/D) polymorphism is characterized by the insertion (I) or deletion (D) of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D) polymorphism was correlated with plasma Ang-(1-7) levels and several RAS components in both preeclamptic (N = 20) and normotensive pregnant women (N = 20). The percentage of the ACE DD genotype (60%) in the preeclamptic group was higher than that for the control group (35%); however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260). The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 +/- 5.06 vs 27.6 +/- 3.25 nmol Hip-His Leu(-1) min(-1) mL(-1) in DD control patients; P = 0.0005). Plasma renin activity was markedly reduced in preeclampsia (0.81 +/- 0.2 vs 3.43 +/- 0.8 ng Ang I mL plasma(-1) h(-1) in DD normotensive patients; P = 0.0012). A reduced plasma level of Ang-(1-7) was also observed in preeclamptic women (15.6 +/- 1.3 vs 22.7 +/- 2.5 pg/mL in the DD control group; P = 0.0146). In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans

Essential hypertension (EH) is considered a typical polygenic disease, so the evaluation of gene-gene interactions rather than the determination of single gene effects is crucial to understanding any genetic influences. The G-protein beta3-subunit (GNB3) 825T allele, associated with enhanced G-protein signalling, is a strong candidate for interactions with polymorphisms, such as insertion/deletion (I/D) polymorphism of angiotensin I-converting enzyme (ACE) gene. We investigated whether there is an association between GNB3 C825T and ACE I/D polymorphisms for the development of EH. We carried out a case-control study of 688 hypertensive and 924 normotensive subjects recruited from South Korea. The GNB3 C825T and ACE I/D genotypes were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods, respectively. The distributions of alleles and genotypes for the GNB3 C825T and ACE I/D polymorphisms were not found to be significantly associated with hypertensive status in either males or females. Logistic regression analysis indicated that the GNB3 825T allele carriers were positively associated with EH in males (odds ratio (OR) for TT/CT, 1.459; 95% confidence interval (CI), 1.048-2.033, P=0.0255). In analysis of gene-gene interaction, we found that there was a significant interaction between the GNB3 825T and ACE D alleles (P<0.05). OR for EH was significantly higher in 825T allele carriers with ACE D allele (OR, 1.490; 95% CI, 1.117-1.987, P=0.0067). A significant interaction between the GNB3 825T and the ACE D alleles may contribute to the predisposing effect for the development of EH in Koreans.

Influences of Chymase and Angiotensin I-Converting Enzyme Gene Polymorphisms on Gastric Cancer Risks in Japan

The renin-angiotensin system plays an important role in homeostasis. Angiotensin II, which is generated by chymase and angiotensin I-converting enzyme (ACE), controls blood pressure as well as angiogenesis and cell proliferation. The aim of this study was to clarify the association of the chymase gene (CMA/B) and ACE polymorphisms with susceptibility to gastric cancer and peptic ulcer. We assessed CMA/B A/G and ACE insertion/deletion (I/D) polymorphisms in H. pylori-positive gastric cancers (n = 119), gastric ulcers (n = 127), and duodenal ulcers (n = 105), and controls (n = 294) consisting of H. pylori-positive gastritis alone (n = 162) and H. pylori-negative subjects (n = 132) by PCR methods. In CMA/B polymorphism, the age- and sex-adjusted odds ratios (OR) of A/A and A/G genotypes relative to the G/G genotype for gastric cancer risk were 7.115 (95% confidence interval, 1.818-27.845) and 1.956 (95% confidence interval, 1.137-3.366), respectively. There was an increased risk for gastric ulcer in the A/A genotype (OR, 3.450; 1.086-10.960). However, there was no association between ACE polymorphism and susceptibility to gastric cancer and peptic ulcer. In allele combination analysis of CMA/B and ACE polymorphisms, the A/I allele combinations (CMA/B G/A or A/A and ACE I/I genotype) significantly increased the risk of gastric cancer development (OR, 4.749, 2.050-11.001) compared with the G/I allele combinations (CMA/B G/G and ACE I/I genotype). The CMA/B polymorphism was associated with an increased risk for gastric cancer and gastric ulcer development. The genotyping test of the renin-angiotensin system could be useful for the screening of individuals with higher risks of gastric cancer and gastric ulcer.

Angiotensin converting enzyme gene polymorphisms do not predict the course of idiopathic nephrotic syndrome in Swiss children

Contradictory reports exist about a correlation of angiotensin I converting enzyme (ACE) gene polymorphisms to the outcome of idiopathic nephrotic syndrome (INS) in children. We investigated the frequency of ACE polymorphisms and their impact on the clinical course of INS in children in a Swiss hospital. The ACE gene polymorphism (I, insertion; D, deletion) was assessed in 32 children - 22 with steroid-sensitive INS and 10 with steroid-resistant INS - with a median age at onset of INS of 2.9 years (range 1.1-15.0). Polymerase chain reaction amplification was performed on genomic DNA isolated from blood leucocytes. Results were correlated to clinical course and renal morphology. The ACE genotype was I/I, I/D and D/D in two, 12 and eight patients, respectively, with steroid-sensitive INS, and in one, eight and one patient, respectively, with steroid resistance. Renal morphology, available in 25 patients showed minimal change glomerulopathy in 17 patients (14 steroid-sensitive; three steroid-resistant) and focal segmental glomerulosclerosis in eight (one steroid-sensitive; seven steroid-resistant). There was no significant correlation between ACE genotype and steroid responsiveness, histology or outcome. ACE genotype was I/I, I/D and D/D in none, 12 and five patients, respectively, with minimal change glomerulopathy, and in one, five and two patients, respectively, with focal segmental glomerulosclerosis. Six patients with steroid-resistant nephrotic syndrome went into end stage renal disease; ACE genotype was I/I in one and I/D in five, but none were D/D. In contrast to previous reports, ACE gene polymorphism is irrelevant for clinical outcome, steroid responsiveness or morphology in Swiss children with INS.

The associations of ACE polymorphisms with physical, physiological and skill parameters in adolescents

Genetic variation in the human Angiotensin I-Converting Enzyme (ACE) gene has been associated with many heritable traits, including physical performance. Herein we report the results of a study of several physical, physiological and skill parameters and lifestyle in 1,027 teenage Greeks. We show that there is a strong association (P < 0.001) between the ACE I/D (insertion/deletion) polymorphism and both handgrip strength and vertical jump in females, homozygotes for the I-allele exhibiting higher performance-related phenotype scores, accounting for up to 4.5% of the phenotypic variance. The association is best explained by a model in which the D-allele is dominant, with the mean phenotypic value in the I/D heterozygotes being close to that of the mean of the DD homozygotes. The association acts across the phenotype distribution in a classical polygenic manner. Other polymorphisms that define major ACE haplotypes in European populations (rs4424958, rs4311) show weaker associations with these performance-related phenotypes than does I/D. Similarly, diplotypes defined by these polymorphisms do not explain significantly larger amounts of the variance than I/D alone. As ACE I/D is the polymorphism most strongly associated with circulating ACE activity in European populations, we propose that the functional allelic differences that influence ACE activity also mediate the associations with the performance-related phenotypes studied here.

Effect of hypertension on angiotensin-(1–7) levels in rats with different angiotensin-I converting enzyme polymorphism

To determine circulating angiotensin-(1–7) [Ang-(1,7)] levels in rats with different angiotensin converting enzyme (ACE) genotypes and to evaluate the effect of hypertension on levels of this heptapeptide, plasma levels of angiotensin II (Ang II) and Ang-(1–7) were determined by HPLC and radioimmunoassay in (a) normotensive F 0 and F 2 homozygous Brown Norway (BN; with high ACE) or Lewis (with low ACE) rats and (b) in hypertensive F 2 homozygous male rats (Goldblatt model). Genotypes were characterized by PCR and plasma ACE activity measured by fluorimetry. Plasma ACE activity was 2-fold higher ( p < 0.05) in homozygous BN compared to homozygous Lewis groups. In the Goldblatt groups, a similar degree of hypertension and left ventricular hypertrophy was observed in rats with both genotypes. Plasma Ang II levels were between 300–400% higher ( p < 0.05) in the BN than in the Lewis rats, without increment in the hypertensive animals. Plasma Ang-(1–7) levels were 75–87% lower in the BN rats ( p < 0.05) and they were significantly higher ( p < 0.05) in the hypertensive rats from both genotypes. Plasma levels of Ang II and Ang-(1–7) levels were inversely correlated in the normotensive rats (r = − 0.64; p < 0.001), but not in the hypertensive animals. We conclude that there is an inverse relationship between circulating levels of Ang II and Ang-(1–7) in rats determined by the ACE gene polymorphism. This inverse relation is due to genetically determined higher ACE activity. Besides, plasma levels of Ang-(1–7) increase in renovascular hypertension.

Reduction of Pneumonia Risk by an Angiotensin I–Converting Enzyme Inhibitor in Elderly Japanese Inpatients According to Insertion/Deletion Polymorphism of the Angiotensin I–Converting Enzyme Gene

We have reported that use of angiotensin I-converting enzyme (ACE) inhibitor, which is a class of antihypertensive agent that induces cough, is an independent factor in reducing risk of pneumonia among elderly inpatients. Insertion/deletion (I/D) polymorphism of the ACE gene (ACE) has been associated with the risk of pneumonia in elderly individuals. However, the ability of ACE inhibitors to reduce pneumonia-related morbidity in individuals with the ACE polymorphism is unclear. Therefore we determined the association of ACE inhibitor use and ACE genotypes with reduction of pneumonia risk in the Japanese elderly population. We conducted a hospital-based, retrospective, case-control study to evaluate the effect of an ACE inhibitor and ACE polymorphism on incidence of pneumonia. Case subjects were pneumonia patients (N = 105) >or=65 years of age, during an 8-month period of a nonwinter season. Control subjects (n = 420) were elderly patients who were frequency matched to the case subjects by age (within +/- 2 years) and gender. Data were collected on medication with the ACE inhibitor temocapril and on known risk factors for pneumonia. The significances of differences for the risk factors were analyzed using univariate and multivariate comparisons of the case and control subjects. After adjustment for potential confounders by multiple logistic regression analysis, the odds ratio (OR) estimates for pneumonia were 0.458 (95% confidential interval [CI]: 0.230 to 0.909, P = .026) for ACE inhibitor use. Conditional logistic regression analysis according to ACE genotypes revealed significant reduction of pneumonia risk by use of temocapril compared with that in nonhypertensive individuals (ie, the reference group) in those with ACE ID + II (OR: 0. 416, 95% CI: 0.177 to 0.976, P = .044), but not in those with ACE DD (OR: 0.706, 95% CI: 0.198 to 2.518, P = .592). These results suggest that use of an ACE inhibitor is beneficial for reducing risk of pneumonia, particularly in individuals with the ACE genotypes ID + II.

Effects of Interaction between Angiotensin I‐Converting Enzyme Polymorphisms and Lifestyle on Adiposity in Adolescent Greeks

Genetic variation in the human angiotensin I-converting enzyme (ACE) gene has been associated with many heritable traits, including obesity. Herein, we report the results of a study of obesity-related phenotypes and lifestyle in 1016 teen-aged Greeks. We show that there is a strong association (p = 0.001) between subcutaneous fat and the ACE insertion/deletion (I/D) polymorphism in females, possession of genotypes containing the D allele being associated with increased fat thickness. This association is strongest in females who participate in no extra exercise and accounts for 6.5% of the phenotypic variance in fat thickness by ANOVA. The association is additive, with the mean phenotypic values in heterozygotes intermediate between the means of the two homozygotes, and the association acts at both extremes of the fat thickness distribution in a classical polygenic manner. Other ACE polymorphisms (rs4424958, rs4311) that define major haplotypes in European populations fail to provide stronger associations with the subcutaneous fat phenotype. Because ACE I/D is the polymorphism most strongly associated with circulating ACE levels in European populations, we propose that the functional allelic differences that influence circulating ACE levels also mediate the associations with the obesity-related phenotypes studied here.

Association of the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients of migraine with aura

Recently, several angiotensin I-converting enzyme (ACE) inhibitors and an angiotensin II receptor blocker were demonstrated to have a clinically important prophylactic effect in migraine. ACE is one of the key enzymes in the rennin–angiotensin–aldosterone system, which modulates vascular tension and blood pressure. In humans, serum ACE levels are strongly genetically determined. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity levels. To investigate the role of ACE polymorphism in headache, we analyzed the ACE insertion (I)/deletion (D) genotypes of 54 patients suffering from migraine with aura (MwA), 122 from migraine without aura, 78 from tension-type headache (TH), and 248 non-headache healthy controls. The ACE D allele were significantly more frequent in the MwA than controls ( p < 0.01). The incidence of the D/D genotype in MwA (25.9%) was significantly higher than that in controls (12.5%; p < 0.01; odds ratio = 5.26, 95% confidence interval: 1.69–16.34, adjusted for age and gender). No differences in the remaining groups were found. Our results support the conclusion that the D allele and the D/D genotype in the ACE gene is a genetic risk factor for Japanese MwA. There seems to be a possible relationship between ACE activity and the pathogenesis of migraine.

Increased Frequency Of An Ace Polymorphism In Ethiopian Elite Marathon Runners

1769 The Angiotensin I-Converting Enzyme (ACE) gene ID polymorphism is defined by the presence (insertion, I) or absence (deletion, D) of a 287 bp fragment in an Alu sequence. There is controversy as to whether this polymorphism is associated with elite athletic performance due to the heterogeneity of the study cohorts with regard to training status, sport and ethnic background. There have been no studies investigating the possible link between the ACE polymorphism and athletic performance in Africans. PURPOSE: To compare the ACE ID genotype of elite Ethiopian athletes to the general Ethiopian population and assess whether the ACE polymorphism is associated with athletic performance. METHODS: DNA was extracted from buccal swabs collected from 114 members of the Ethiopian national athletics team, 109 individuals representative of the general Ethiopian population (C), and 99 individuals from Arsi (R), a region renowned for athletic success. Athletes belonged to three groups: Marathon (M; n = 34), 5,000–10,000 m (5–10 km; n = 42) and other track and field athletes (TF; n = 38). The ACE ID genotype was determined using a 3-primer PCR system. Group differences were analysed using contingency chi-square tests. RESULTS: Genotypes of elite Ethiopian male marathoners differed from Ethiopian males, with a higher proportion of ACE II homozygotes in marathoners relative to controls (M: 22.7 %; C: 4.3 %; p = 0.023). No other genotype differences were found. Allele frequencies of male marathoners also differed from Ethiopian males, with a greater proportion of I alleles in marathoners relative to controls (M: 0.43; C: 0.26; p = 0.044). No other allele frequency differences were found in males (R: 0.35; 5–10 km: 0.40; TF: 0.36) or females (R: 0.39; 5–10 km: 0.42; TF: 0.23). CONCLUSION: A higher ACE II genotype and I allele frequency was found in elite Ethiopian male marathoners compared to the general Ethiopian male population. This may be a reflection of the region of Arsi where the majority of male marathoners originate. Research part-funded by The Royal Society, The Carnegie Trust for the Universities of Scotland, and The Wellcome Trust