Relationship between polymorphisms in the renin-angiotensin system and nephropathy in type 2 diabetic patients

BACKGROUND: Renin Angiotensin system is involved in renal function and its polymorphisms may influence diabetic nephropathy. ID ACE polymorphism modulates ACE level whereas M235T AGT polymorphism is involved in arterial hypertension. The A1166C AT1R polymorphism is involved in arterial hypertension and in diabetic retinopathy.METHODS: Two hundred thirty five type 2 diabetic patients were enrolled in this transversal study. Data were documented for clinical characteristics of the population, HbA(1c), urinary albumin excretion, presence of retinopathy or antihypertensive treatment. Polymorphisms were analyzed by PCR techniques. The patients were divided into 3 groups: group 1, without nephropathy (n=118), group 2, microalbuminuria (n=78), group 3, macroalbuminuria (n=39).RESULTS: Diabetes duration was longer (p<0.001), retinopathy (p<0.001) and antihypertensive treatment (p<0.02) were more frequent in group 3 compared to group 1 and 2. The I/D ACE and M235T AGT polymorphisms were not differently distributed between the three groups. In contrast, the CC genotype of the AT1R polymorphism was overrepresented in group 2 (p=0.021). The presence of the CC AT1R genotype considerably increased the incidence of albuminuria after 10 years of diabetes (AA vs CC p=0.01), particurlarly in men. No effect was seen with I/D ACE and M235T AGT polymorphisms.CONCLUSION: In conclusion, we observed an interaction of A1166C AT1R polymorphism with diabetes in men but not of I/D ACE and M235T AGT polymorphisms.     

Association of the renin-angiotensin system gene polymorphism with nephropathy in type II diabetes

Diabetic nephropathy is the most frequent cause of end-stage renal failure. One of the crucial factors in a development of renal and cardiovascular complications of diabetes is genetic predisposition. The genes of the renin-angiotensin system are important group of candidate genes involved in pathogenesis of chronic renal diseases. The purpose of our study was the evaluation of a possible role of genetic polymorphisms of some of the RAS system genes in the nephropathy in type 2 diabetes. The study was performed in 117 patients with diabetic nephropathy, compared with 200 healthy subjects as a control group. The following polymorphisms: insertion/deletion (I/D) of the angiotensin-converting enzyme gene (ACE), M235T of the angiotensinogen gene (AGT) and A1166C of the angiotensin II type 1 receptor gene (AT1R) were evaluated by polymerase chain reaction (PCR). No statistically significant differences between groups were found in the allele frequency and genotype distribution for ACE and AGT polymorphisms. The results for the AT1R gene polymorphism revealed significant differences in allele and genotype frequencies. The homozygous CC genotype was more frequent in patients with diabetic nephropathy than in control group. Both genotypes with the C allele (AC + CC) were found in 56% of patients compared to 38% in control group. These results suggest increased susceptibility to diabetic nephropathy in individuals carrying the CC genotype. Therefore, the A1166C polymorphism of the AT1R gene could be a potential genetic marker for increased susceptibility to renal complications in type 2 diabetes.     

Genetic variants of the renin-angiotensin system, diabetic nephropathy and hypertension

Summary Recent studies have suggested an association between a deletion (D) variant of the angiotensin-converting-enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. The objective of our study was therefore to examine the relationship between these genetic variants of the renin-angiotensin system and diabetic nephropathy and hypertension, respectively, in a large (n = 661) group of Caucasian patients with insulin-dependent (n = 360) or non-insulin-dependent (n = 301) diabetes mellitus. The study had a power of 0.8 to detect a doubling of risk of nephropathy or hypertension in patients with the ACE-DD or AGT-235TT genotype, respectively. Allelic frequencies of the ACE-D and AGT-235T alleles were similar between patients with and without nephropathy in either type of diabetes, and accordingly, there was no significant association between diabetic nephropathy and the ACE or AGT genotype. Likewise, there was no significant association between the ACE or AGT genotype and hypertension. Thus, our data, in this large and ethnically homogeneous group of patients, do not support the hypothesis that these genetic variants of the renin-angiotensin system are strongly associated with either nephropathy or hypertension in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. These genetic markers are therefore unlikely to serve as clinically useful predictors of either nephropathy or hypertension in Caucasian patients with diabetes. [Diabetologia (1997) 40: 193–199] Received: 16 July 1996 and in revised form: 17 October 1996     

Genetic polymorphisms of angiotensin-I converting enzyme, haptoglobin and angiotensinogen and oxidative stress parameters in 12 to 15-year-old adolescents.

BACKGROUND: Angiotensin-converting enzyme (ACE) I/D, haptoglobin (Hp) 1/2 and angiotensinogen (AGT) M235T gene polymorphisms have been associated with the risk of various cardiovascular conditions. Oxidative stress and reactive oxygen species have also been implicated in endothelial injury. In a randomly selected sample of healthy adolescents, we studied the relationship between these genetic polymorphisms and somatic characteristics, blood pressure and certain biochemical markers of oxidative stress. METHODS: A sample of 49 healthy adolescents were genotyped for ACE I/D, Hp 1/2 and AGT M235T polymorphisms. Anthropometric parameters, blood pressure and lipid profile were evaluated using internationally recommended methods. Serum ACE activity and oxidative stress markers were determined either by spectrophotometric methods or with commercially available kits. RESULTS: Males had higher values for ACE activity than females (p < 0.01). The haptoglobin Hp allele 1 and the ACE D allele were associated with higher ACE activity (p < 0.05 and p < 0.001). ACE activity was similar between AGT genotypes. Higher levels of MDA-LDL/Apo B were observed in individuals with both ACE DD and Hp 2-2 genotypes. Carriers of the AGT TT genotype showed higher diastolic blood pressures than other AGT genotypes. CONCLUSION: Carriers of both ACE DD and Hp 2-2 genotypes have a higher pro-oxidant status and AGT TT carriers have higher diastolic blood pressures, which may indicate a higher risk for development of hypertension in these individuals.     

Polymorphisms of the renin-angiotensin system genes in Brazilian patients with lupus nephropathy

Genetic polymorphisms of the renin-angiotensin system (RAS) has been associated with cardiovascular events and the progression of nephropathy in several diseases. The objective of this study was to evaluate a possible association of the genetic polymorphisms of RAS with the development and/or progression of lupus nephritis in a Brazilian population. Seventy-five SLE patients with lupus nephropathy (LN group) were compared to 72 SLE patients without LN (SLE group) and 65 healthy individuals (CONTROL group), of sex and ethnic matched, in a Brazilian population sample. Mean global follow-up was 9 +/- 6 years for lupus without nephropathy and 11 +/- 7 years for lupus nephropathy. Following the extraction of genomic DNA from the leukocytes in the peripheral blood, angiotensin converting enzyme (ACE I/D), angiotensinogen (AGT M(235)T) and angiotensin II type 1 receptor (AGTR1 A(1166)C) genotypes were determined by the polymerase chain reaction. No significant difference of ACE, AGT and AGTR1 genotypes distribution between groups was observed in this study. There was no significant association between the variables of the RAS genotypes and the presence of hypertension in SLE. However, an increased frequency ofDD genotype (ACE I/D) was observed in SLE patients with LN who progressed to CRF compared to healthy controls (DD 60%, DI 26.7%, II 13.3% versus 27.7%, 60% and 12.3%, respectively; chi2 = 6.299, P = 0.0429). In the population studied, there was no influence of the RAS genetic polymorphisms in the development of lupus nephropathy, but the progression to CRF was associated with ACE DD polymorphism.     

Association of angiotensinogen M235T and A(-6)G gene polymorphisms with coronary heart disease with independence of essential hypertension: the PROCAGENE study. Prospective Cardiac Gene

OBJECTIVES: We examined the relationship between the angiotensinogen (AGT) gene M235T polymorphism, the variant promoter of the AGT gene A(-6)G and the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and coronary heart disease (CHD) in native Gran Canaria Island habitants, who have the highest rates of CHD in Spain. BACKGROUND: Some studies subject that the ACE (I/D) polymorphism could be associated with CHD, while AGT (M235T) has been related to essential hypertension. METHODS: We studied 304 subjects with angiographic evidence of coronary artery disease and a clinical diagnosis of myocardial infarction or unstable angina and 315 age- and gender-matched controls. Blood was drawn and DNA extracted. Angiotensin-converting enzyme (I/D) gene polymorphism was analyzed by polymerase chain reaction (PCR) and AGT gene polymorphisms by restriction fragment length polymorphism-PCR and mutagenically-separated PCR. RESULTS: The ACE (I/D) polymorphism showed no association with CHD, whereas the frequency distribution of AGT (M235T) genotypes among patients and controls (235T: 29.1% and 19.0%; M235T: 48.5% and 50.2%; M235: 22.4% and 30.8%, respectively) was statistically different (p = 0.005) and not related to the presence of essential hypertension. Similar results were observed with the AGT A(-6)G polymorphism. In multiple logistic regression analysis, CHD odds ratio associated with 235T and M235 homozygotes were 1.7 (1.1 to 2.6) and 0.54 (0.36 to 0.82), respectively. CONCLUSIONS: This study shows that genetic variation of the AGT (M235T), but not the ACE (I/D), genotypes contributes to the presence of CHD independently of blood pressure profile in a subset of the Spanish population with a high prevalence of cardiovascular disease.     

Angiotensinogen M235T polymorphism and left ventricular indices in treated hypertensive patients with normal coronary arteries.

OBJECTIVE: Hypertension and left ventricular hypertrophy (LVH) are important causes of morbidity and mortality in the population. Angiotensinogen (AGT) M235T polymorphism has been associated with LVH, left ventricular dimensions, coronary artery disease and antihypertensive drug response in previous studies. We examined relationship between AGT M235T polymorphism and echocardiographic left ventricular indices in a Turkish population of treated hypertensive patients with normal coronary arteries. METHODS: In this cross-sectional study a Turkish population of 92 hypertensive patients treated in our outpatient clinic were enrolled. All patients had normal coronary angiographic examinations. Genotypes for AGT M235T were determined from peripheral leukocytes. Left ventricular dimensions, mass and function indices, after adjustment for clinical covariates were analyzed by multiple regression analysis according to genotypes. RESULTS: Genotype frequencies for AGT M235T were MM-24.7%, MT-52.8% and TT-22.5%. Left ventricular end-systolic (LVES) dimensions for AGT M235T MM, MT, TT genotypes were 17.9+/-4.2 mm, 19.4+/-6.2 mm, and 16.4+/-2.9 mm, respectively (p=0.08). Angiotensinogen M235T TT genotype showed a trend towards a lower LVES dimension but results were not statistically significant. Left ventricular ejection fractions for AGT M235T MM, MT, TT subgroups were 61.3+/-15.0%, 59.4+/-14.0%, and 67.8+/-8.5%, respectively (p=0.07). Angiotensinogen M235T TT genotype showed a tendency towards lower left ventricular mass index but results were not statistically significant. None of the AGT M235T genotypes predicted left ventricular dilatation, mass or function in treated hypertensive patients with normal coronary arteries. CONCLUSION: Angiotensinogen M235T polymorphism was not useful to predict left ventricular mass, function, hypertrophy or dilatation in a small population of treated Turkish hypertensive patients with normal coronary arteries.     

Angiotensinogen gene T235 variant: a marker for the development of persistent microalbuminuria in children and adolescents with type 1 diabetes mellitus

AIM: We examined genetic polymorphisms in the renin-angiotensin system (RAS) coding for angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) for angiotensinogen (AGT) M235T and angiotensin II receptor type 1 (AGTR1) A1166C as predictors for the development of microalbuminuria (MA) in children with type 1 diabetes mellitus (T1DM). METHODS: Four hundred fifty-three (215 males, 238 females) T1DM children [median (interquartile range): age, 16.7 years (13.9-18.3); diabetes duration, 6.9 years (3.3-10.8); age at diagnosis, 9.1 years (5.8-11.8)] were followed prospectively from diagnosis until the development of MA (two of three consecutive overnight urine samples with albumin excretion rates of > or =20 and <200 microg/min). Kaplan-Meier survival curves and Cox proportional multivariate model estimated the probability of developing MA and the relative risk for MA among different variables. RESULTS: MA developed in 41 (9.1%) subjects. The frequencies of genotypes were as follows: ACE-II 112 (25%), ACE-ID 221 (49%), and ACE-DD 117 (26%) (n=450); AGT-MM 144 (32%), AGT-MT 231 (51%), and AGT-TT 77 (17%) (n=452); AGTR1-AA 211 (47%), AGTR1-AC 204 (45%), and AGTR1-CC 37 (8%) (n=452). The cumulative risk for the development of MA was higher in ACE-DD versus ACE-ID/II groups (log-rank test, P=.05), and a trend was noticed when AGT-TT was compared to AGT-MT/MM groups (log-rank test, P=.08). AGT-TT polymorphism conferred a fourfold increased risk for MA compared to AGT-MM/MT (hazard ratio=3.8; 95% confidence interval=1.43-10.3; P=.008). INTERPRETATION: Our findings suggest that RAS gene polymorphism at AGT M235T is a strong predictor for early MA in young T1DM subjects.     

Polymorphism in the angiotensin converting enzyme but not in the angiotensinogen gene is associated with hypertension and type 2 diabetes: the Skaraborg Hypertension and diabetes project

OBJECTIVE: To study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population. PATIENTS AND METHODS: The insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study. RESULTS: The DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09-2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, CI = 1.01-2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, CI = 1.09-4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3'-microsatellite polymorphism of the AGT gene and hypertension. CONCLUSION: The D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3'-microsatellite polymorphism of the AGT gene and hypertension.     

The relationship of the methylenetetrahydrofolate reductase C677T gene polymorphism in Turkish type 2 diabetic patients with and without nephropathy

BACKGROUND: Poor glycaemic control, hypertension and duration of diabetes are risk factors for the development of diabetic nephropathy, but there may be genetic factors. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677C > T) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. We aim to investigate Turkish type 2 diabetic patients with/without diabetic nephropathy and healthy group and examine the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy. METHODS: DNA was extracted from peripheral leukocytes of the subjects. Genotyping of the MTHFR C677T polymorphism for all individuals was performed by melting curve analysis of the generated amplicons after real-time online PCR. RESULTS: This genotype distribution did not differ between control subjects and type 2 diabetic patients in which 6.8% were TT, 43.7% were CT and 49.5% were CC (chi2 = 0.201, p > 0.05). The frequency of the mutant T allele was 23.4% in diabetic patients with nephropathy versus 33.0% in those without nephropathy. The genotype frequencies were TT, 2.1%; CT, 46.6%; CC, 55.3% in diabetic patients with nephropathy versus TT, 10.7%; CT, 44.6%; CC, 44.6% in those without nephropathy. CONCLUSIONS: The MTHFR genotype and allele frequencies were not different between diabetic patients with and without nephropathy (chi2 = 3, 386, p > 0.005; chi2 = 2.320, p > 0.005, respectively). Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Turkish type 2 diabetic patients.     

Renin Angiotensin System Gene Polymorphisms Modify Angiotensin‐Converting Enzyme Inhibitors' Effect on Cognitive Function: The Health,Aging and Body Composition Study

OBJECTIVES: To investigate the effect of polymorphisms in renin angiotensin system genes on the association between angiotensin‐converting enzyme inhibitor (ACEI) exposure and global and executive cognitive function in the Health, Aging and Body Composition study. DESIGN: Cohort study. SETTING: Community. PARTICIPANTS: Three thousand seventy‐five participants: mean age 73.6, 58% Caucasian, 52% female, 15% taking ACE‐Is, 8 years of follow‐up. MEASUREMENTS: The outcomes were longitudinal change in Executive Clock Drawing Test‐1 (CLOX1), the Digit Symbol Substitution test, and the Modified Mini‐Mental State Examination. The genetic polymorphisms included angiotensin‐converting enzyme insertion deletion (ACEID) in the ACE gene and the M235T and 6AG polymorphisms in the angiotensinogen (AGT) gene. RESULTS: For the CLOX1 outcome, there was significant interaction between 6AG and M235T polymorphisms in the AGT gene and angiotensin‐converting enzyme inhibitors (ACE‐Is) in Caucasian participants (P=.01 for both polymorphisms) independent of blood pressure levels. Specifically, ACE‐I exposure was protective against CLOX1 score decline in carriers of the AA genotype of the 6AG and the CC genotype of the M235T (for the ACE‐I vs non‐ACE‐I groups, P=.01 for 6AG and P=.005 for M235T) but not the other genotypes. These associations were not significant with other cognitive tests, with ACEID, or in African Americans. CONCLUSION: ACE‐Is may provide a protective effect on executive function in Caucasians with AGT gene polymorphisms known to be associated with greater renin angiotensin system activity. If confirmed in a pharmacogenetic trial, ACE‐Is may be found to have additional cognitive protection in a select group of elderly individuals.     

肾素-血管紧张素系统双基因多态性与高血压合并舒张性心力衰竭的关系

目的探讨中国南方部分汉族高血压患者肾素一血管紧张素系统中血管紧张素转换酶（ACE）及血管紧张素原（AGT）双基因多态性与舒张性心力衰竭发病的关系。方法应用聚合酶链反应及限制性片断长度多态性技术,对432例高血压患者的ACE基因插入／缺失（I／D）及AGTM235T多态性进行检测。将其中207例合并舒张性心力衰竭者作为病例组,其余225例心功能正常者作为对照组。结果①病例组DD基因型及D等位基因的频率均高于对照组;②病例组TT基因型及T等位基因的频率与对照组比较差异无统计学意义;③联合分析ACE与ACT基因多态性显示,两组中同时具有DD型ACE基因及TT型AGT基因的频率分别为29．0％及14．9％,前者明显高于后者。结论DD型ACE基因可能是该地区高血压患者舒张性心力衰竭发病的遗传危险因素,ACE和AGT基因在慢性心力衰竭的发生中具有协同作用。     

Angiotensin converting enzyme (ACE) gene polymorphism increases the susceptibility of diabetic nephropathy in Western Indian Type 2 diabetic patients

Angiotensin-converting enzyme (ACE) gene has been associated with the pathogenesis and progression of chronic kidney diseases. Diabetic nephropathy has become leading cause of renal end stage disease (ESRD). An I/D polymorphism of angiotensin-converting enzyme (ACE) gene has been suggested as one of the risk factors for the progression of diabetic nephropathy. We analyzed the genotype and allele frequency distribution of ACE gene in 166 Type 2 diabetic patients without any complication (T2DM), 61 with diabetic nephropathy (DN), 50 with non-diabetic nephropathy (NDN) and 50 healthy individuals from western Indian population. ACE genotype was analyzed by PCR method. The D allele distribution for the ACE I/D polymorphisms was not significantly different between control group and patients with T2DM without any complication (41.0% vs. 45.2%, P?=?0.461) and between control subjects and patients with non-diabetic nephropathy (NDN) (41.0% vs. 44.0%, P?=?0.668). Frequency of the D allele (63.9% vs. 45.2%, P?<?0.001) and DD genotype (I allele noncarrier) (44.3% vs. 25.3%, P?=?0.006) of ACE gene was significantly higher in patients with diabetic nephropathy (DN) than in patients with T2DM without any complication. Results of the present study indicate that ACE gene polymorphism does not have significant influence on development of diabetes mellitus and nondiabetic nephropathy, whereas, the DD polymorphism in ACE gene has been associated with the development of diabetic nephropathy in the Western Indian population.     

Angiotensinogen T174M and M235T gene polymorphisms are associated with the extent of coronary atherosclerosis.

BACKGROUND: The relations of the angiotensinogen (AGT) T174M and M235T gene polymorphisms to the risk of coronary heart disease (CHD) have been investigated in only a few studies with conflicting results. RESULTS: Therefore, we analysed the relationship of the AGT gene polymorphisms to the presence and extent of CHD in 2250 male Caucasians whose coronary anatomy was defined by means of coronary angiography. The relative frequencies of the T and M alleles of the T174M and of the M235T gene variation did not significantly differ between patients without or with single-, double- or triple-vessel disease and between subjects without or with myocardial infarction (MI). In contrast the mean CHD score--defined by Gensini--was higher within MM homozygotes of the T174M gene variation than within TT genotypes; TM subjects had intermediate values. In M235T genotypes, mean CHD scores were similar in the total sample and in older individuals (> or = 62 years), whereas in younger individuals (< 62 years) a higher CHD score was found within AGT 235 T allele carriers than within MM homozygotes. In younger individuals with high apoAI plasma levels, the mean CHD score was clearly higher within TT homozygotes of the M235T gene variation than within MM genotypes; MT subjects had intermediate values. An interaction between both angiotensinogen gene polymorphisms on the extent of CHD or on the risk of non-fatal MI were not observed when the M allele of AGT T174M was combined either with the T allele or the TT genotype of M235T. CONCLUSIONS: The present study strengthens the hypothesis of an association of both angiotensinogen gene polymorphisms with the extent of coronary heart disease.     

2型糖尿病肾病与血管紧张素转换酶基因多态性的研究

目的 探讨２型糖尿病肾病与ＡＣＥ基因Ｉ／Ｄ多态性。方法 应用ＰＣＲ方法检测了３６例健康对照者、５８例糖尿病肾病和５０例有糖尿病肾病、病程大于５年的２型糖尿病病人的ＡＣＥ基因Ｉ／Ｄ基因型。结果 三组间ＡＣＥ基因ＩＩ、ＩＤ、ＤＤ三种基因型和Ｉ、Ｄ两种等位基因的频率分布无显著性差异;在三种基因型之间,尿白蛋白排泄率和血肌酐水平也无显著性差异。结论 ＡＣＥ基因Ｉ／Ｄ多态生与中国汉族２型糖尿病肾病无关联,Ａ     

Angiotensinogen gene polymorphism (Met235Thr) influences visceral obesity and insulin resistance in obese Japanese women

To investigate the relationship between angiotensinogen (AGT) Met235Thr polymorphism (M235T) and human obesity, because AGT is regarded as one of the cytokines produced from adipocytes and serum AGT concentrations are reported to be positively correlated with body mass index. One hundred and twenty obese Japanese women (age, 58.8+/-9.4 years; body mass index, 32.2+/-4.9 kg/m(2)) were enrolled. Angiotensinogen genotypes were determined with a fluorescent allele-specific DNA primer assay system. Subjects were divided into M/M, M/T, and T/T groups. Control subjects comprised 146 healthy age-matched women. Clinical characteristics and the effects of diet and exercise therapy for 6 months were compared among the 3 genotypes. The genotype frequencies of AGT M235T polymorphism were in accordance with the Hardy-Weinberg equation (obese: M/M, 6.7%; M/T, 27.5%; T/T, 65.8%; control: M/M, 6.8%; M/T, 21.2%; T/T, 71.9%). The frequency of the T allele did not differ between obese and control subjects (0.80 vs 0.83). As the number of obese women with M/M genotype was only 8, comparisons of the characteristics and outcomes of weight reduction therapy were performed only between subjects with M/T genotype and T/T genotype. In the T/T group, % body fat and waist circumference at baseline were significantly greater than in the M/T group (36.3%+/-4.8% vs 33.8%+/-4.7%, P=.0105; 107.9+/-10.9 vs 102.6+/-7.9 cm, P=.0428, respectively). Before the weight reduction therapy, significantly higher insulin and higher homeostasis model assessment (HOMA-R) were demonstrated in the T/T group than in the M/T group (9.1+/-5.5 microU/mL vs 5.9+/-4.4 microU/mL, P=.0056; 2.3+/-1.4 vs 1.6+/-1.3, P=.0252, respectively). Both systolic and diastolic blood pressure at baseline in the T/T group tended to be higher than those in the M/T group, but the differences were not significant. No genotype-dependent difference in energy expenditure or outcome of weight reduction therapy was observed with respect to AGT M235T polymorphism. After the diet and exercise therapy, the blood pressure in the T/T group tended to be higher than that in the M/T group, but the difference was not significant. We demonstrated that the T/T genotype of the AGT M235T gene polymorphism was positively related to visceral obesity and hyperinsulinemia in obese Japanese women. Blood pressure did not show genotype-specific differences before or after the treatment. Further studies of the association between obesity and this gene polymorphism should contribute to understanding and treating obesity-related diseases.     

Peripheral vascular disease in Type 2 diabetic Chinese patients: associations with metabolic indices, concomitant vascular disease and genetic factors.

AIMS: Conventional and genetic risk factors have been reported to play a role in the pathogenesis of vascular disease, but do not explain the lower burden of cardiac and peripheral vascular disease (PVD) in Chinese compared with Caucasians. The role of renin-angiotensin system (RAS) gene polymorphisms and conventional vascular risk factors has not been determined. METHODS: A total of 3097 Chinese diabetic subjects were screened for PVD, which was identified in 194 of the 2967 patients with Type 2 diabetes. Biochemical parameters and the genotype and allele frequencies of three RAS gene polymorphisms, the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms were then compared between the PVD patients and 1046 age, gender and diabetes duration-matched patients without PVD. RESULTS: PVD identified in 6.5% was associated with significantly worse glycaemic control, lipid profile and renal function. Smoking was more common, as were the other macro- and microvascular diseases. The prevalence of hypertension was similar between the groups, yet diastolic blood pressure was slightly lower in the PVD group. The ACE D allele was significantly more frequent in patients with PVD compared with the matched diabetic controls (38.1 vs. 29.8%, P = 0.039). No differences in the AT1R or AGT polymorphisms were observed. CONCLUSIONS: PVD was associated with a worse metabolic profile and greater concomitant vascular disease than controls. The ACE I/D polymorphism was associated with PVD in these Type 2 diabetic patients.     

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms are non-randomly distributed in oral contraceptive-induced hypertension

OBJECTIVES AND METHODS: Oral contraceptives (OC) usage increases serum angiotensinogen levels to three to five times normal and about 5% of these women develop arterial hypertension. The genetic contribution to this susceptibility to OC-induced hypertension is poorly understood. We have analyzed the genotypes of 149 hypertensive and 101 normotensive women using oral contraceptives, for three genetic polymorphisms in genes of the renin-angiotensin system: an insertion/deletion (I/ D) in the angiotensin converting enzyme (ACE) gene, the T235M polymorphism of the angiotensinogen gene (AGT) and a point mutation in its promoter. RESULTS: After cessation of oral contraception the mean arterial pressures of the hypertensive women were separable into two non-overlapping groups; 88 of the women remained hypertensive and 61 returned to normal blood pressure. Both groups of hypertensive women had a similarly higher frequency of hypertensive relatives than the normotensive women, but were otherwise similar. The 235T allele of AGT was significantly increased in frequency in the 61 oral contraceptive-inducible hypertensive women compared with the controls and the 88 women that remained hypertensive. The ACE I/D genotypes were similarly distributed within the three groups of women, but were distinctly non-random in the oral contraceptive-induced hypertensive women when they were also classified by AGT genotype. CONCLUSION: This statistical interaction of genotype frequencies suggests that the genetic basis of susceptibility to OC-induced hypertension is complex.     

Progression of kidney disease in type 2 diabetes – beyond blood pressure control: an observational study

Background

Essential hypertension is a common, polygenic, complex disorder resulting from interaction of several genes with each other and with environmental factors such as obesity, dietary salt intake, and alcohol consumption. Since the underlying genetic pathways remain elusive, currently most studies focus on the genes coding for proteins that regulate blood pressure as their physiological role makes them prime suspects. The present study examines how polymorphisms of the insertion/deletion (I/D) ACE and M235T AGT genes account for presence and severity of hypertension, and embeds the data in a meta-analysis of relevant studies.

Methods

The I/D polymorphisms of the ACE and M235T polymorphisms of the AGT genes were determined by RFLP (restriction fragment length polymorphism) and restriction analysis in 638 hypertensive patients and 720 normotensive local blood donors in Weisswasser, Germany. Severity of hypertension was estimated by the number of antihypertensive drugs used.

Results

No difference was observed in the allele frequencies and genotype distributions of ACE gene polymorphisms between the two groups, whereas AGT TT homozygotes were more frequent in controls (4.6% vs. 2.7%, P =.08). This became significant (p = 0.035) in women only. AGT TT genotype was associated with a 48% decrease in the risk of having hypertension (odds ratio: 0.52; 95% CI, 0.28 to 0.96), and this risk decreased more significantly in women (odds ratio: 0.28; 95% CI, 0.1 to 0.78). The meta-analysis showed a pooled odds ratio for hypertension of 1.21 (TT vs. MM, 95% CI: 1.11 to 1.32) in Caucasians. No correlation was found between severity of hypertension and a specific genotype.

Conclusion

The ACE I/D polymorphism does not contribute to the presence and severity of essential hypertension, while the AGT M235T TT genotype confers a significantly decreased risk for the development of hypertension in the population studied here. This contrasts to the findings of meta-analyses, whereby the T allele is associated with increased risk for hypertension.     

Angiotensin-converting enzyme gene polymorphism and microvascular complications in Turkish type 2 diabetic patients

The aim of this study was to investigate whether an association exists between the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and microvascular complications of type 2 diabetes mellitus in Turkish patients. A total of 239 type 2 diabetic patients and 138 sex and age matched control subjects were included into the study. The I/D polymorphism was determined by polymerase chain reaction (PCR). Nephropathy status was determined according to urinary albumin/creatinine ratio (microg/mg) (<30 normoalbuminuria, 30-300 microalbuminuria, >300 macroalbuminuria) and retinopathy was evaluated by fundoscopic examination and by flourescein fundus angiography. The distribution of ACE I/D polymorphism and allele frequencies in diabetic patients were not significantly different from controls, DD genotype 32.2 versus 37.2%; ID genotype 50.6 versus 47.1%; and II 17.2 versus 15.2%; D allele 57.5 versus 61.2%; I allele 42.5 versus 38.8%. Genotype distribution between normo-, micro- and macroalbuminuric patients did not differ significantly (DD:ID:II (%), normoalbuminuria, 35:46:19; microalbuminuria, 28:55:17; macroalbuminuria, 31:55:14). There was also no difference in genotype distribution between patients with and without retinopathy (DD:ID:II (%), retinopathy positive, 32:51:17; retinopathy negative, 33:49:18). In conclusion, the ACE I/D polymorphism does not seem to be associated with diabetic nephropathy and retinopathy in Turkish type 2 diabetic patients.