血管紧张素转换酶基因多态性与糖尿病及其肾脏合并症发病的关系

目的探讨血管紧张素转换酶（ＡＣＥ）基因插入／缺失（Ｉ／Ｄ）多态性与Ⅱ型糖尿病（ＮＩＤＤＭ）及其肾脏合并症发病的关系。方法应用聚合酶链反应（ＰＣＲ）扩增技术检测了１０９例ＮＩＤＤＭ患者及１５５例健康对照者的ＡＣＥ基因Ｉ／Ｄ多态性。结果位于ＡＣＥ基因第１６内含子的Ｉ／Ｄ多态性经ＰＣＲ技术扩增后分为三种基因型：纯合子缺失型（ＤＤ）,纯合子插入型（Ｉ）及杂合子插入／缺失型（ＩＤ）。１０９例ＮＩＤＤＭ患者与１５５例正常对照组之间基因型及等位基因频率差异均无显著意义;ＮＩＤＤＭ合并肾病者（ＤＮ）的基因型与未合并肾病者无显著性差异,但等位基因则有显著性差异（Ｄ、Ｉ等位基因为０４５和０５５对０３０和０７０）（Ｐ＜００２）;ＮＩＤＤＭ病程≤１年即伴有肾病者与病程≥５年仍无肾病者比较,ＤＤ型及Ｄ等位基因均显著高于无肾病组（Ｐ均＜００５）,后者以Ｉ型及Ｉ等位基因占绝对优势。结论ＡＣＥ基因多态性与ＮＩＤＤＭ发病无关,而与其肾脏合并症则明显相关,ＤＤ型是ＤＮ的易感基因,而Ｉ型则为其保护基因。     

血管紧张素-Ⅰ转换酶基因多态性与糖尿病及糖尿病肾病的关系

目的　探讨血管紧张素Ⅰ转换酶基因（ＡＣＥ基因） 多态性与糖尿病及糖尿病肾病（ＤＮ） 的易感性之间的关系。方法　应用聚合酶链式反应（ＰＣＲ）方法扩增４８ 例正常人、７４ 例胰岛素依赖型糖尿病（ＩＤＤＭ） 患者（ 其中４０ 例不伴ＤＮ,３４ 例合并ＤＮ） 、１０２ 例非胰岛素依赖型糖尿病（ＮＩＤＤＭ） 患者（５７ 例不伴ＤＮ,４５ 例伴ＤＮ） 的ＡＣＥ基因上２８７ｂｐ 片断,根据插入（Ｉ） 或缺失（Ｄ） 来判断其多态性。结果　健康对照组与ＩＤＤＭ 及ＮＩＤＤＭ 组ＡＣＥ 等位基因、基因型均无显著性差异（ Ｐ＞０－０５）;在ＩＤＤＭ 组中,Ｄ等位基因及ＤＤ基因型在伴ＤＮ亚组中显著升高;在ＮＩＤＤＭ 组中,与不伴ＤＮ者比较,伴ＤＮ者其Ｉ等位基因、ＩＩ基因型频率明显为低。结论ＡＣＥ 基因多态性与糖尿病易感性无关,与ＤＮ密切相关。     

血管紧张素—Ⅰ转换酶基因多态性与糖尿病与糖尿病肾病的关系

目的 探讨血管紧张素－Ⅰ转换酶基因（ＡＣＥ基因）多态性与糖尿病及糖尿病肾病（ＤＮ）的易感性之间的关系。方法 应用聚合酶链式反应（ＰＣＲ）方法扩增４８例正常人，７４例胰岛素依赖型糖尿病（ＩＤＤＭ）患者（其中４０例不伴ＤＮ，３４例合并ＤＮ），１０２例非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者（５７例不伴ＤＮ，４５例伴ＤＮ）的ＡＣＥ基因上２８７ｂｐ片断，根据插入或缺失来判断其多态性。     

糖尿病患者骨代谢研究

本文测定７４例糖尿病住院患者的血Ｃａ、Ｐ、ＡＫＰ、ＢＧＰ、２４小时尿ＨＯＰ及腰椎２～４正位骨密度（ＢＭＤ）。结果（１）糖尿病患者血Ｃａ、Ｐ、ＡＫＰ与正常对照无显著差异，并且胰岛素依赖型糖尿病组（ＩＤＤＭ）与非胰岛素依赖型糖尿病组（ＮＩＤＤＭ）之间也无显著差异。（２）血ＢＧＰ变化，在ＩＤＤＭ组，２０～３９岁的女性和４０～５９岁的男性ＢＧＰ低于正常对照；ＮＩＤＤＭ组６０岁以上的女性患者ＢＧＰ也明显低于正常对照，而在２０～３９岁的男女患者ＢＧＰ却高于正常对照。（３）糖尿病患者尿ＨＯＰ高于正常对照，并且ＩＤＤＭ组与ＮＩＤＤＭ组比较也有显著差异。（４）骨质疏松发生率ＩＤＤＭ组高于ＮＩＤＤＭ组，而骨量减低发生率ＮＩＤＤＭ组高于ＩＤＤＭ组。初步探讨了糖尿病性骨质疏松的发病机制。     

Ⅱ型糖尿病并发肾病患者Apo E基因多态性研究

目的 研究糖尿病肾病发生，发展的遗传学倾向，寻找与ＤＮ发病有关的基因。方法 采用ＰＣＲ－ＲＥＬＰ技术，研究了９７例Ⅱ型糖尿病患者ＡｐｏＥ基因多态性与ＤＮ及其脂代谢异常的关系。结果 （１）ＤＮ组ε２等位基因频率明显高于糖尿病组及正常组；在尿白蛋白排泄率〉２００μｇ／ｍｉｎ组和２０－２００ｇ／ｍｉｎ之间Ａｐｏ Ｅ基因频率无明显差异。（２）携ε２等位基因的ＤＭ患者甘油三酯水平明显高于携ε３组，而胆固醇Ｃ     

非胰岛素依赖型糖尿病家族遗传性与胰岛素基因的实验探讨

用分子生物学的实验方法对非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者的胰岛素基因进行检测。从ＮＩＤＤＭ患者（包括有糖尿病家族史）及正常人外周血的白细胞中提取ＤＮＡ，以胰岛素基因５＇－末端上游的某一ＤＮＡ序列做引物，对特定的靶序列进行体外扩增（即ＰＣＲ），将其扩增产物进行电泳分离，并在紫外分析仪下对照观察，结果发现：１６例ＮＩＤＤＭ患者的胰岛素基因有所改变，其中２例患者及１例末发病同胞兄弟的胰岛素基因有相     

糖尿病纤维连接蛋白血小板聚集功能改变临床分析

为探讨ＮＩＤＤＭ患者Ｆｎ、ＰＡＧ改变与缺血性心脑血管病的关系，分析５３例ＮＩＤＤＭ患者Ｆｕ、ＰＡＧ测定结果，并与５３名健康人比较。患者组Ｆｎ明显高于（Ｐ〈０．０１），前者ＰＡＧ（１）、ＭＡＲ、Ｉ与后者有显著统计学差异（Ｐ〈０．０１）。患者组中并发症组与无并发症组Ｆｎ、Ｉ较对照组有明显统计学差异（Ｐ〈０．０１），并发症组ＰＡＧ（１）、ＭＡＲ明显高于对照组（Ｐ〈０．０５）。ＮＩＤＤＭ患者Ｆｎ降低、ＰＡ     

ACE基因多态性与2型糖尿病肾病关系的研究

目的：明确血管紧张素Ｉ转换酶（ＡＣＥ）基因插入／缺失（Ｉ／Ｄ）多态性与２型尿病及其肾病发生及进展的关系。方法：ＡＣＥ基因内含子１６的一个２８７ｂｐ的Ａｌｕ顺序Ｉ／Ｄ型为多态标志，用聚合酶链反应（ＰＣＲ）扩增基因片段，１％琼脂糖凝胶电泳检测ＰＣＲ产物。结果：（１）２２１例２例糖尿病与１００例正常对照组之间基因型分布无显著性差异；（２）２型糖尿病未合并肾病与合并肾病及肾功不全（ＲＦ）等各亚组之间基因型频率和等位基因频率无显著性差异。结论：ＡＣＥＩ／Ｄ多态性与２型糖尿病肾病和肾功能不全的发生无关。     

Ⅱ型糖尿病肾病患者β_3-肾上腺素能受体基因多态性研究

目的 探讨β３－肾上腺素能受体（β３－ＡＲ）基因６４位点的色氨酸（Ｔｒｐ）密码子被精氨酸（Ａｒｇ）置换与糖尿病肾病（ＤＮ）之间的关系。方法 采用聚合酶链反应－限制性片段长度多态性（ＰＣＲ－ＲＥＬＰ）技术,研究了１９６例Ⅱ型糖尿病患者β３－ＡＲ基因Ｔｒｐ６４Ａｒｇ突变基因型,并测体重指数（ＢＭＩ）、血压、尿微量白蛋白排泄率（ＵＡＥＲ）、空腹血脂、血糖、糖化血红蛋白Ａ１ｃ（ＨｂＡ１ｃ）、空腹及餐后２ｈＣ肽。结果（１）中国上海地区Ⅱ型糖尿病患者Ａｒｇ６４等位基因频率为０．１３,低于印第安人（Ｐ＜０．００１）和日本人（Ｐ＜０．０１）,略高于芬兰人（Ｐ＞０．０５）。（２）糖尿病患者中,Ａｒｇ６４携带者组ＢＭＩ、血甘油三酯水平明显高于非携带者组（Ｐ＜０．０５）,而发病年龄、确诊糖尿病时年龄、病程、血压、空腹血糖、ＨｂＡ１ｃ、空腹及餐后２ｈＣ肽、总胆固醇、高密度脂蛋白及低密度脂蛋白水平,两组无明显差别。（３）ＤＮ组Ａｒｇ６４等位基因频率为０．１８,明显高于非ＤＮ组（Ｐ＜０．０１）,且与ＤＮ分期无关。结论 中国上海地区Ⅱ型糖尿病患者β３－ＡＲ基因Ｔｒｇ６４Ａｒｇ突变与体内脂肪分布及脂代谢紊乱有关;Ａｒｇ６４等位基因可能是ＤＮ的     

胰岛素依赖型糖尿病肾病患者红细胞膜钠锂交换活性测定及意义

探讨红细胞膜钠锂交换活性（ＳＬＣＡ）与胰岛素依赖型糖尿病（ＩＤＤＭ）肾病之间的关系。方法采用Ｃａｎｅｓｓａ建立的方法，测定了１３例ＩＤＤＭ肾病，以及性别、年龄、糖尿病病程和体重指数（ＢＭＩ）等匹配的１２例正常白蛋白尿ＩＤＤＭ患者红细胞膜ＳＬＣＡ。结果ＩＤＤＭ肾病红细胞膜ＳＬＣＡ０．４６（０．３７～０．５４）ｍｍｏｌ·Ｌ－１·ＲＢＣ－１／ｈ显著高于正常白蛋白尿ＩＤＤＭ患者ＳＬＣＡ０．３０（０．２１～０．３９）ｍｍｏｌ·Ｌ－１·ＲＢＣ－１／ｈ（Ｐ＜０．００１）。结论ＳＬＣＡ可能是预测ＩＤＤＭ肾病最早的指标     

Increased frequency of angiotensin-converting enzyme DD genotype in patients with type 2 diabetes in Taiwan.

BACKGROUND: Diabetes is one of the major causes of end-stage renal failure in the Taiwanese population. Previous studies have shown that angiotensin-converting enzyme (ACE) inhibitor can improve glucose utilization and suppress hepatic glucose production and the renin-angiotensin system may play an important role in the initiation and progression of diabetic nephropathy. Thus, ACE gene polymorphism may be associated with type 2 diabetes and diabetic nephropathy. METHODS: To investigate the distribution of ACE-I/D genotype in type 2 diabetes and diabetic nephropathy, we examined 336 patients with type 2 diabetes (157 without nephropathy and 179 with nephropathy) and 263 age-matched normal controls. The diagnosis of nephropathy was made when daily protein loss exceeded 500 mg. ACE gene polymorphism was analysed by use of polymerase chain reaction. RESULTS: Our study revealed that the frequency of the D allele of the ACE gene was 29.3% in normal controls. The frequency of ACE DD genotype was significantly higher in type 2 diabetics compared with normal controls (18.2 vs 9.1%, P<0.01). The frequency of ACE DD genotype in patients with diabetic nephropathy was significantly higher than in patients without nephropathy (22.3 vs 13.4%, P<0.05). To determine whether ACE gene polymorphism was associated with the severity of diabetic nephropathy, we divided patients with diabetic nephropathy into dialysis and non-dialysis groups. The frequency of ACE DD genotype in the dialysis group was significantly higher than in non-dialysis group (28.7 vs 15.3%, P<0.05). CONCLUSION: Our results indicate that the frequency of ACE DD genotype is markedly higher in patients with type 2 diabetes, and the ACE DD genotype is significantly associated with diabetic nephropathy.     

ACE gene polymorphism and the prognosis and treatment of overt diabetic nephropathy

An insertion (I)/deletion (D) polymorphism of the angiotensin-converting-enzyme (ACE) gene influences the circulating and renal activity of the renin-angiotensin-aldosterone system. This Practice Point commentary discusses a 2008 paper by Parving et al. that analyzed the interaction between losartan and the I/D polymorphism in patients in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. The investigators found that patients with type 2 diabetes and proteinuria who have the D allele have an unfavorable renal prognosis, which is improved by losartan treatment (vs placebo) when given together with conventional antihypertensive treatment. No significant improvement in outcomes was observed in losartan-treated patients with the II genotype. Previous observational studies had suggested a decreased beneficial effect of ACE inhibitors in patients with type 1 diabetic nephropathy who have the DD genotype. Prospective studies in this area are needed before I/D genotype characterization can be used to guide the choice of therapy in patients with diabetes and proteinuria.     

Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study

Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its insertion/deletion (I/D) polymorphism, which determines most of ACE interindividual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact with ACE I/D polymorphism for the risk of diabetic nephropathy, but their prognostic values have to be established by follow-up studies. A total of 310 type 1 diabetes mellitus patients who attended the diabetic clinic in Angers (France) took part in a prospective, observational, follow-up study. Glycohemoglobin, BP, plasma creatinine, and urinary albumin excretion were determined periodically. Nephropathy was classified as absent, incipient (microalbuminuria), established (proteinuria), advanced (plasma creatinine > or = 150 micromol/L), and terminal (renal replacement therapy). The main end point was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal events was significantly influenced by ACE genotype (log-rank II versus ID versus DD, P < 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, baseline plasma ACE concentration was higher in patients who progressed to microalbuminuria (571 +/- 231 versus 466 +/- 181 microg/L; P = 0.0032); the D allele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributors were male gender, baseline systolic BP, and urinary albumin excretion. The AGT M235T polymorphism was not associated with renal events. The D allele of the ACE I/D polymorphism is an independent risk factor for both the onset and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.     

Excess of DD homozygotes in haemodialysed patients with type II diabetes. The Diabetic Nephropathy Study Group

The role of the insertion/deletion polymorphism of the angiotensin- converting enzyme (ACE) gene in the genesis of diabetic nephropathy has been controversial. It has recently been proposed that progression occurs more rapidly in individuals with diabetic and non-diabetic renal disease who are homozygous for the D allele. We studied 658 patients with type II diabetes, 347 without diabetic nephropathy and 311 with various stages of diabetic nephropathy, and determined the I/D polymorphism of the ACE gene. Patients at the extremes of renal risk, i.e. normotensive patients without antihypertensive treatment and without nephropathy (n = 144), vs patients on dialysis (n = 61), differed with respect to genotype (DD 36.8% vs 57.4%; P = 0.007) and allele frequencies (D 0.59 vs 0.76; P < 0.001). In contrast, patients with and without presumed nephropathy as assessed by albuminuria did not differ with respect to DD genotype. In conclusion, in this study, which was limited by sample size, patients with the highest renal risk more frequently had the DD genotype. This would be compatible with a greater risk of (or rate of) progression to end-stage renal failure.      

Angiotensin converting enzyme gene insertion/deletion polymorphism in idiopathic nephrotic syndrome in Kuwaiti Arab children

OBJECTIVE: Angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influence the circulating and cellular levels of ACE and has been shown to be a risk factor in a number of diseases including IgA nephropathy. We have investigated the association of ACE gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome (INS) in Kuwaiti children. MATERIALS AND METHODS: The genotypes for ACE gene I/D polymorphism were determined in 102 subjects (54 INS cases and 48 healthy controls) using a PCR method. RESULTS: The distribution of DD, ID and II genotypes was 70%, 20% and 10% in INS cases compared with 52%, 46% and 2% in the controls. The mean age of onset of the disease was significantly lower in the INS cases with DD genotype (37 months) compared with cases with II genotype (65 months, p < 0.05). The clinical manifestation of the disease was considerably severe in cases with DD genotypes compared with cases having ID and II genotypes. The INS cases with DD genotype also showed a significantly higher incidence of steroid sensitivity and steroid dependence. Seventy-three per cent of the INS cases with minimal change lesion had a DD genotype. Also 70% of the cases which needed cytotoxic drugs had DD genotype. CONCLUSION: Our data suggest an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation of INS in Kuwaiti Arab children.     

Relationship between polymorphism in the angiotensinogen, angiotensin-converting enzyme or angiotensin II receptor and renal progression in Japanese NIDDM patients.

We determined the relationship between the gene polymorphism of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), or angiotensin II receptor (AT1R) and the progression of diabetic nephropathy in a multicenter trial of ethnically homogeneous Japanese patients with non-insulin-dependent diabetes (NIDDM). Gene polymorphism of ACE I/D, AGT M235T and AT1R A1166C was determined by polymerase chain reaction amplification using allele-specific primers. Japanese NIDDM patients (n = 1,152) were selected from several diabetic clinics. All patients were divided into three groups as follows: (1) group I (n = 407): normoalbuminuric patients; (2) group II (n = 327): microalbuminuric patients, and (3) group III (n = 418): overt albuminuric patients. Clinical factors for investigation in all patients were the date of birth, gender, levels of urinary albumin excretion, findings of the ocular fundus, duration of diabetes, hemoglobin A1c and blood pressure. It appears that genetic polymorphisms in the renin-angiotensin systems, i.e. ACE or AT1R, may affect the progression to renal failure of patients (especially females) with NIDDM.     

Deletion polymorphism in the angiotensin I converting enzyme (ACE) gene as a genetic risk factor for sarcoidosis.

BACKGROUND: Genetic control of serum angiotensin I converting enzyme (SACE) levels has been suggested. A study was undertaken to elucidate the role of this polymorphism in sarcoidosis. METHODS: Three hundred and forty one unrelated healthy controls and 103 consecutive patients with sarcoidosis participated in the study. SACE levels and an insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene were studied in each subject and new reference intervals for SACE activity for each genotype were determined. The difference in genotype and allele frequencies between controls and patients was analysed and odds ratios were calculated to estimate the relative risk. RESULTS: A significant association was seen between ACE gene polymorphism and SACE levels in both patients and controls. The new reference intervals for each genotype discriminated abnormal SACE levels in patients more accurately, especially those with genotype II. In women the frequencies of allele I were 0.68 (allele D 0.32) in controls and 0.58 (allele D 0.42) in patients, and the difference between the two female groups was significant (p < 0.05). Thus, an excess of genotype ID or DD was observed in female patients (odds ratio 2.18; 95% confidence interval 1.18 to 4.01; p = 0.01). CONCLUSIONS: These findings suggest that ACE gene polymorphism is associated with SACE levels in both patients with sarcoidosis and controls. ACE gene polymorphism should be further evaluated as a candidate marker for an increased risk of sarcoidosis.     

Polymorphisms of renin-angiotensin system genes in childhood IgA nephropathy

We investigated whether polymorphisms of the renin-angiotensin system genes are involved in IgA nephropathy in Japanese children. We identified the M235T polymorphism of the angiotensinogen (AGT) gene, the I/D polymorphisms of the angiotensin-converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor gene in 95 Japanese children with IgA nephropathy and 99 healthy Japanese adults. There were no differences in the genotype and allele frequencies of these genes between patients with IgA nephropathy and controls. Urinary protein excretion at the time of biopsy was significantly greater in patients with the TT genotype of the AGT gene than in those with the MM/MT genotypes of the AGT gene (1.32± 1.42 versus 0.75±0.78 g/day; P=0.01) and in patients with the ID/DD genotypes of the ACE gene than in those with the II genotype of the ACE gene (1.45±1.50 versus 0.63±0.56 g/day; P=0.001). Thus, the TT genotype of the AGT gene and the ID/DD genotype of the ACE gene are associated with increased severity of proteinuria, suggesting that AGT and ACE gene polymorphisms may play a significant role in the progression of IgA nephropathy in Japanese children. Received: 21 July 2000 / Revised: 8 December 2000 / Accepted: 11 December 2000