血管紧张素转换酶基因缺失纯合型与糖尿病肾病相关联

应用ＰＣＲ扩增方法检测２０３例ＮＩＤＤＭ患者和１６５例正常对照者血管紧张素（ＡＣＥ）基因的１６内含子中２８７ｂｐ片段缺失／插入多态性。结果显示,糖尿病肾病患者组ＡＣＥ基因缺失纯合型（ＤＤ）频率明显高于非肾病组和正常对照组,Ｐ〈０．００１;ＤＤ缺失纯合型患者肾病进展速度明显快于缺失／插入（ＤＩ）杂合型及插入／插入（ＩＩ）纯合型糖尿病患者,Ｐ〈０．０１。表明ＡＣＥ基因缺失纯合型是糖尿病肾病的独立危险因     

Interdependent effect of angiotensin-converting enzyme and platelet-activating factor acetylhydrolase gene polymorphisms on the progression of immunoglobulin A nephropathy

In order to investigate the interdependent action of the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene and polymorphism in exon 11 (C1136-->T; Ala379Val) of the platelet-activating factor acetylhydrolase (PAF-AH) gene, which encodes a functional antagonist of PAF, on the progression of immunoglobulin A (IgA) nephropathy, we analysed both polymorphisms in patients with primary IgA nephropathy, who were followed-up for longer than 3 years. During the follow-up (87.3 +/- 50.0 months), the disease progressed in 38 of the 191 patients (19.9%). The D allele of the ACE gene in the absence of the T allele of the PAF-AH gene did not affect the prognosis [odds ratio (OR), 3.6; 95% confidence interval (CI), 0.8-16.4] and neither did the T allele in the absence of the D allele (OR, 3.0; 95% CI, 0.4-24.2). However, the presence of both was a significant prognostic factor (OR, 6.6; 95% CI, 1.4-31.3). After adjusting for other risk factors, the presence of both proved to be an independent risk factor (OR, 4.5; 95% CI, 1.6-12.7). These results suggest that the interdependent effects of ACE and PAF-AH polymorphisms on the progression of IgA nephropathy might be more important than the effect of the individual polymorphisms.     

1型和2型糖尿病视网膜病与血管紧张素Ⅰ转换酶基因多态性关联研究

目的探讨血管紧张素Ⅰ转换酶(ACE)基因多态性与糖尿病视网膜病之间关联.方法应用PCR技术,对Ⅰ型糖尿病33名视网膜病患者、36名非视网膜病患者和2型糖尿病57名视网膜病患者、190名非视网膜病患者的ACE基因插入/缺失(Ⅰ/D)型多态性进行了检测.结果与结论未证明1型和2型糖尿病时ACE基因和视网膜病之间关联.     

Association between polymorphism of the angiotensin I converting enzyme gene and hypertension in Turkish type II diabetic patients

It has been suggested that an insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin converting enzyme (ACE) gene may be associated with essential hypertension. The aim of this study was to examine the association between ACE I/D polymorphism with blood pressure level and hypertension status in Turkish type 2' diabetic subjects. Hundred and seven hypertensive (78 female, 29 male) and 132 normotensive type 2 diabetic subjects (73 female, 59 male) and 138 sex and age matched control subjects (87 female, 51 male) without diabetes and hypertension were included into the study. The I/D polymorphism was determined by polymerase chain reaction (PCR). There were no statistically difference in genotypic and allelic frequencies of the ACE I/D polymorphism between the hypertensive and normotensive diabetic patients and control subjects. Also no significant differences was detected in systolic and diastolic blood pressure among three different genotypes. ACE I/D polymorphism does not seem to play an important role in the development of hypertension in Turkish type 2 diabetic subjects, but prospective studies may show an association between ACE gene polymorphism and the development of hypertension in diabetic subjects.     

Molecular screening of the human glutamine-fructose-6-phosphate amidotransferase 1 (GFPT1) gene and association studies with diabetes and diabetic nephropathy

Increased glucose metabolism through the hexosamine pathway may result in insulin resistance, impaired insulin secretion, and diabetic nephropathy. We hypothesized that variants of GFPT1 encoding glutamine-fructose-6-phosphate amidotransferase, the rate limiting enzyme in this pathway, could increase GFPT1 gene expression and thus susceptibility to diabetes and diabetic nephropathy. To test this hypothesis, we screened for variation in the GFPT1 and flanking regions in Caucasian and African-American individuals. We tested each variant with over 5% allele frequency for an association with type 2 diabetes in Caucasian and African-American populations, and for an association with diabetic nephropathy in African-American subjects. We measured allele specific levels of GFPT1 mRNA and we compared mRNA levels across diagnostic categories for each ethnic group using RNA derived from transformed lymphocytes. None of the 8 variants detected altered the coding sequence or was present in a known regulatory region. We found a marginal association (p = 0.044) of 1/6 variants with diabetes in Caucasian subjects, and marginal associations of 2/7 variants with diabetic nephropathy among African-American subjects (p = 0.025, p = 0.041). Alleles marked by a variant in the 3' untranslated region were equally expressed, but in a small sample, GFPT1 mRNA levels were increased by 60% in Caucasians with diabetic nephropathy compared to diabetic individuals without nephropathy. Variants in the GFPT1 gene show suggestive evidence of an association with diabetic nephropathy among African-American individuals, and increased GFPT1 gene expression may characterize Caucasian subjects with diabetic nephropathy. Both findings need to be confirmed in other populations.     

Cardiovascular risk factors in people with different genotypes in the insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme (ACE)

The deletion (D) allele of an insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme (ACE) has been reported to be an independent risk factor for myocardial infarction (MI), particularly in people lacking traditional risk factors. Furthermore, a borderline association between Lp(a) lipoprotein level and the I/D polymorphism at the ACE locus was reported in one study. We have searched for possible "level gene" or "variability gene" effects of ACE genes on Lp(a) lipoprotein, total cholesterol (TC), high density lipoprotein (HDL) cholesterol (HDLC), low density lipoprotein (LDL) cholesterol (LDLC), triglycerides (TG), apolipoprotein B (apoB), apolipoprotein A-I (apoA-I), and body mass index (BMI). None of these variables differed significantly between genotypes in the I/D polymorphism in any of three population samples. A single population sample created by combining the three series, exhibited an insignificant trend towards individuals carrying the D-allele having a higher level of Lp(a) lipoprotein than those lacking it, and DD homozygotes had a significantly higher Lp(a) lipoprotein level than the combined group of ID/II individuals (p = 0.03). These results may indicate that the D-allele of the I/D polymorphism at the ACE locus could influence the level of Lp(a) lipoprotein.     

Association of polymorphisms in monocyte chemoattractant protein-1 promoter with diabetic kidney failure in Korean patients with type 2 diabetes mellitus

Monocyte chemoattractant protein-1 (MCP-1) is suggested to be involved in the progression of diabetic nephropathy. We investigated the association of the -2518 A/G polymorphism in the MCP-1 gene with progressive kidney failure in Korean patients with type 2 diabetes mellitus (DM). We investigated -2518 A/G polymorphism of the MCP-1 gene in type 2 DM patients with progressive kidney failure (n=112) compared with matched type 2 DM patients without nephropathy (diabetic control, n=112) and healthy controls (n=230). The overall genotypic distribution of -2518 A/G in the MCP-1 gene was not different in patients with type 2 DM compared to healthy controls. Although the genotype was not significantly different between the patients with kidney failure and the diabetic control (p=0.07), the A allele was more frequent in patients with kidney failure than in DM controls (42.0 vs. 32.1%, p=0.03). The carriage of A allele was significantly associated with kidney failure (68.8 vs. 54.5%, OR 1.84, 95% CI 1.07-3.18). In logistic regression analysis, carriage of A allele retained a significant association with diabetic kidney failure. Our result shows that the -2518 A allele of the MCP-1 gene is associated with kidney failure in Korean patients with type 2 DM.     

The C825T polymorphism in the G-protein β3 subunit gene and diabetic complications in IDDM patients

Complications of insulin-dependent diabetes mellitus (IDDM) are a major cause of morbidity and mortality; however, the mechanisms of their development are still to be elucidated. Genetic susceptibility contributes to the pathogenesis of nephropathy in IDDM. Enhanced G-protein activation, a cellular phenotype observed in cultured cells from patients with essential hypertension, was recently documented in IDDM subjects with nephropathy. A C825T polymorphism was recently described in GNB3, the gene encoding the beta 3 subunit of heterotrimeric G-proteins. This genetic variant has been associated with enhanced G-protein activation. The 825T allele was observed more frequently in a group with essential hypertension. We analyzed the role of the C825T polymorphism in the predisposition to diabetic complications in IDDM. In this study, we investigated the frequency of this polymorphism in a large case-control study and found no association of the 825T allele with diabetic nephropathy, retinopathy, and neuropathy. Received: July 14, 2000 / Accepted: January 4, 2001     

The angiotensin-I converting enzyme (ACE) gene I/D polymorphism and ACE levels in Pima Indians.

An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is associated with plasma ACE levels in white populations. The occurrence of the I/D polymorphism and relationship to ACE levels was examined in a Pima Indian group (n = 305). The frequency of the D allele was lower in Pimas than whites (0.29 v 0.52 respectively). ACE levels were significantly associated with genotype in both groups (p = 0.0001), which accounted for 6.5% of the variation in ACE levels in Pimas and 18% in whites. The association of the I/D polymorphism with ACE levels confirms the relationship across ethnic groups. The low frequency of the D allele in Pima Indians shows that ethnic differences should be accounted for when studying the ACE gene.     

Angiotensin-converting enzyme gene polymorphism in patients with systemic lupus

The renin-angiotensin-aldosterone system (RAAS) has been considered one of the probable pathophysiologic mechanisms involved in disease progression. Genetic polymorphism of the RAAS has been associated with the clinical course of renal disease. One of the genetic polymorphisms is a deletion or insertion of a 287 base pair fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. It is known that ACE gene polymorphism is present in humans and that it is associated with an increased risk of cardiovascular diseases, renal disease progression and sarcoidosis. In this study, the potential significance of ACE gene polymorphism in patients with systemic lupus erythematosus (SLE) was investigated. ACE gene polymorphism was determined in 18 patients with SLE and in 21 healthy volunteers as a control group. The mean age of patients was 38.5 years. All patients had a mean follow-up of 30.7 +/- 20.2 months (range 5-95 months). ACE genotypes were determined by the method of polymerase chain reaction. Proteinuria and creatinine were also followed. The frequency of DD, ID and II genotypes was 50%, 28% and 22% in SLE patients and 25%, 50% and 25% in healthy controls, respectively. DD genotype was more common in SLE patients than in the control group. The patients with II genotype had lower proteinuria and creatinine level than those with DD genotype (p < 0.05). The time to disease remission was shorter in patients with II genotype (p < 0.05). Study results indicated an increased frequency of D allele in SLE patients. The increased ACE activity in these patients pointed to the need of further studies of ACE gene polymorphism in SLE.     

Lack of association between angiotensin converting enzyme polymorphism and sporadic Alzheimer's disease

Epidemiological and pathogenetic evidences suggest a strong association between vascular risk factors and sporadic Alzheimer's disease (sAD). In agreement with the vascular hypothesis of AD, the role of various candidate genes for atherosclerosis has been investigated, leading to conflicting results. In order to clarify the significance of angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism in a group of patients with sAD, we conducted a case-control study including 149 cases and 149 age and sex matched controls. All subjects were genotyped for ACE and Apolipoprotein E (APOE). There were no significant differences in ACE genotype or allele frequencies between cases and controls, even after stratification for APOE4 carrier status. Our data suggest that the ACE I/D polymorphism is not associated to genetic susceptibility in sAD patients.     

血管紧张素Ⅰ转换酶基因多态性与糖尿病视网膜病和糖尿病心肌梗塞关联

目的　探讨血管紧张素 转换酶 ( angiotensin - converting enzyme,ACE)基因多态性与糖尿病视网膜病和心肌梗塞之间的关联性。方法　应用 PCR技术 ,对 1型糖尿病 33例视网膜病患者和 36例非视网膜病患者、2型糖尿病 6 8例伴心肌梗塞患者和 5 7例伴视网膜病患者以及 190例无并发症患者的ACE基因插入 /缺失型多态性进行了检测。结果　 ACE基因与视网膜病之间无关联。而 2型糖尿病心肌梗塞患者与非心肌梗塞患者比较 ,DD纯合子频率显著增高 ( 4 1.2 % vs 33.2 % ) ,D等位基因频率也显著增高 ,差异有显著性 ( P<0 .0 5 )。结论　 D等位基因 (相对风险为 1.5 0 )和 DD基因型 (相对风险为 1.33)可能是 2型糖尿病心肌梗塞发生的风险因子     

血管紧张素I转换酶基因多态性与糖尿病视网膜病和糖尿病心肌梗塞关联

目的探讨血管紧张素Ⅰ转换酶(angiotensin Ⅰ-converting enzyme, ACE)基因多态性与糖尿病视网膜病和心肌梗塞之间的关联性.方法应用PCR技术,对1型糖尿病33例视网膜病患者和36例非视网膜病患者、2型糖尿病68例伴心肌梗塞患者和57例伴视网膜病患者以及190例无并发症患者的ACE基因插入/缺失型多态性进行了检测.结果 ACE基因与视网膜病之间无关联.而2型糖尿病心肌梗塞患者与非心肌梗塞患者比较, DD纯合子频率显著增高(41.2% vs 33.2%),D等位基因频率也显著增高,差异有显著性(P<0.05).结论 D等位基因(相对风险为1.50)和DD基因型(相对风险为1.33)可能是2型糖尿病心肌梗塞发生的风险因子.     

Association of variants in the carnosine peptidase 1 gene (CNDP1) with diabetic nephropathy in American Indians

CNDP1 is located on 18q22.3, where linkage with diabetic nephropathy has been observed in several populations, including Pima Indians. However, evidence for association between CNDP1 alleles and diabetic nephropathy is equivocal and population-dependent. This study investigated CNDP1 as a candidate for diabetic kidney disease in Pima Indians. Nineteen tag single nucleotide polymorphisms spanning the CNDP1 locus were selected using genotype data from Chinese individuals in the HapMap resource along with 2 variants previously associated with diabetic nephropathy. All variants were genotyped in 3 different samples including a diabetic end-stage renal disease (ESRD) case-control study, a family-based study of diabetic individuals who participated in the linkage study for nephropathy, and a cohort of diabetic individuals in whom longitudinal measures of glomerular filtration rates (GFR) were performed. There was no statistically significant evidence for association with diabetic ESRD. However, nominal evidence for association was found in the family study, where markers rs12957330 (Odds ratio [OR]=0.29 per copy of G allele; p=0.04) and rs17817077 (OR=0.46 per copy of G allele; p=0.05) were associated with diabetic nephropathy. In addition, markers rs12964454, rs7244647, and rs7229005 were associated with changes in GFR (-8.5ml/min per copy of the G allele; p=0.04; 18.8ml/min per copy of the C allele; p=0.03; and -13.4ml/min per copy of the C allele; p=0.001, respectively). These findings provide nominal evidence supporting a role between CNDP1 variants and diabetic kidney disease.     

PPARγ2基因Pro12Ala多态性与DM2-N易患性的关系

目的:研究我国北方汉族人群PPARγ2基因Pro12Ala多态性与2型糖尿病肾病(DM2-N)易患性的关系.方法:应用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法检测了78例2型糖尿病(DM2)患者(糖尿病肾病组患者41例,非糖尿病肾病组患者37例)及38例正常对照组的PPARγ2基因Pro12Ala多...     

The -106CC genotype of the aldose reductase gene is associated with an increased risk of proliferative diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes

Diabetic retinopathy is a sight-threatening chronic complication of diabetes mellitus and is the leading cause of acquired blindness in adults. The -106C>T polymorphism in the promoter region of the aldose reductase (AR) gene has been shown to be associated with the susceptibility to diabetic nephropathy in type 2 diabetes, but the findings regarding the occurrence of diabetic retinopathy are conflicting. In this case-control study, we investigated whether the -106C>T polymorphism in the AR gene is involved in the development and progression of diabetic retinopathy in 579 Brazilians with type 2 diabetes (424 Caucasian- and 155 African-Brazilians). Patients underwent a clinical and laboratory evaluation consisting of a questionnaire, physical examination, assessment of diabetic complications and laboratory tests. Genotype analysis was performed using the polymerase chain reaction followed by digestion with restriction enzyme. Logistic regression analysis was used to control for independent risk factors associated with diabetic retinopathy. There were no differences in either genotype or allele frequencies for the -106C>T polymorphism between type 2 diabetic patients with or without diabetic retinopathy, in both ethnic groups. However, the CC genotype was associated with an increased risk of having proliferative diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes (odds ratio (OR)=2.04; 95% confidence interval (CI)=1.21-3.45; P=0.007), independently of other risk factors associated with this complication. Thus, our results show that the -106CC genotype (-106C>T polymorphism) in the AR gene is related to the progression of diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes.     

Genetic variation of the angiotensin-converting enzyme gene: increased frequency of the insertion allele in Koreans

In view of the clinical importance of angiotensin-converting enzyme (ACE) as a major marker for cardiovascular diseases, we investigated insertion/deletion ( I/D ) polymorphism of the ACE gene in Koreans. Genotype frequencies were examined by polymerase chain reaction in 171 patients with coronary artery disease (CAD) and 120 healthy subjects. Allele frequencies of ACE polymorphism in Koreans were not significantly different between patient and control groups. In addition, association between ACE genotypes and the number of stenosed coronary arteries was not detected. ACE genotypes in the CAD group were not associated with body mass index and plasma lipid levels. Thus, our results suggest that, at least in Koreans, I/D polymorphism of the gene is unlikely to be a useful marker for CAD subjects. However, the I allele frequency of Koreans (0.58) was higher than that of Caucasian populations (0.47) but lower than that of Samoan (0.91) and Yanomami (0.85) populations. Here, we discuss the clinical and ethnic importance of ACE polymorphism.     

Increased frequency of apolipoprotein ε2 allele in non-insulin dependent diabetic (NIDDM) patients with nephropathy

The genetic polymorphism of apolipoprotein E (ε2, ε3 and ε4) is associated with lipid abnormalities. It has been suggested that lipid abnormalities may contribute to the development and progression of kidney diseases, including diabetic nephropathy. Thus, in this study we compared the apo E allele frequencies among 146 non-insulin-dependent diabetic (NIDDM) patients with nephropathy, 135 NIDDM patients without nephropathy and 576 of the general Japanese population. The ε2 allele frequency was significantly higher in diabetic patients with nephropathy (7.2%) and with renal failure (9.7%) than in diabetic patients without nephropathy (2.6%) and in the general Japanese population (3.7%). It is concluded that there is a possibility that the ε2 allele is associated with nephropathy in NIDDM.     

Angiotensin-converting enzyme gene I/D polymorphism and renal disease

In recent years a vast amount of data has been published on the association between the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin-converting enzyme and renal disease. It has become clear that the polymorphism does not affect the prevalence of renal disease. However, data on the association with progression of renal disease and therapy response are still contradictory. Moreover, sufficient data on the physiological significance of this polymorphism are still lacking. This contribution provides an overview of the available studies and the potential pitfalls in interpreting the data. We also discuss the putative mechanisms for the association between the DD genotype and progression of renal disease and suggest directions for the future that might be employed to further clarify the role in renal pathophysiology.