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.     

Association of transforming growth factor-beta (TGF-beta) T869C (Leu 10Pro) gene polymorphisms with type 2 diabetic nephropathy in Chinese

INTRODUCTION: Transforming growth factor-beta (TGF-beta) is known to play a pivotal role in the regulation of extracellular matrix (ECM) accumulation. Since diabetic nephropathy (DMN) is characterized by basement membrane thickening and mesangial expansion, control of ECM deposition is believed to be important in the pathogenesis of the disease. Recently, TGF-beta T869C (Leu 10Pro) gene polymorphism has been identified which may be associated with circulating TGF-beta levels. METHODS: In order to examine the relationship between TGF-beta gene polymorphism with DMN in Chinese, we carried out a case-control study, which recruited 123 Chinese type 2 diabetic patients with an average duration of diabetes for 12 years. A total of 58 patients who developed DMN (micro- or macroalbuminuria, with or without renal impairment) were compared with 65 diabetic patients without DMN despite similar duration of disease (normoalbuminuric and creatinine <120 micromol/L). TGF-beta T869C (Leu 10Pro) gene polymorphism was determined by polymerase chain reaction (PCR). RESULTS: Both groups of patients had similar baseline characteristics, including blood pressure, diabetic control, and duration of diabetes. Distribution of TGF-beta T869C (Leu 10Pro) genotype among the whole group is confined to Hardy Weinberg equilibrium. The DMN+ group has higher frequency of TGF-beta CC/CT genotypes than the DMN- group [CC, CT, TT = (DMN+) 46, 45, 9 (%) vs. (DMN-) 37, 37, 26 (%), P < 0.05]. C allele frequency is also higher in the DMN+ group than DMN- group (69% vs. 55%, P < 0.05). The adjusted odds ratio for TGF-beta CC/CT vs. TT genotype to develop DMN is 3.8 (3.2 to 4.4). Multivariate logistic regression analysis [hypertension, gender, age, duration of diabetes, hemoglobin (HbA1c), usage of angiotensin-converting enzyme (ACE) inhibitor, and cholesterol level] showed that TGF-beta genotype (P = 0.03) is an independent predictor for type 2 DMN. Among patients with DMN, those with TGF-beta CC/CT genotypes also had worse renal function and increased risk for macroalbuminuria. CONCLUSION: Our results suggest that TGF-beta T869C (Leu 10Pro) gene polymorphism is associated with DMN in Chinese.     

Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study

The development and progression of microvascular complications have been extensively documented in a cohort of type 1 diabetic subjects enrolled in the Diabetes Control and Complications Trial (DCCT) and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. We describe the association of genetic variation in the ACE gene in 1,365 DCCT/EDIC subjects with incident persistent microalbuminuria (n = 312) and severe nephropathy (n = 115). We studied three markers (rs1800764, insertion/deletion, and rs9896208) in the ACE gene that allowed us to capture genetic variation in the common haplotypes occurring at frequencies of >5% in Caucasians. Compared with the more frequent genotype (D/I) for the insertion/deletion polymorphism, in multivariate models, the I/I genotype conferred a lower risk for persistent microalbuminuria (hazard ratio [HR] 0.62 [95% CI 0.43-0.89], P = 0.009) and severe nephropathy (0.56 [0.32-0.96], P = 0.033). Variation at the two other markers, rs1800764 and rs9896208, were also associated with these renal outcomes. In addition, homozygosity for the common haplotype TIC (which corresponded to the T, insertion, and C alleles at the three markers, rs1800764, insertion/deletion, and rs9896208, respectively) versus the CDT/TIC haplotype pair was associated with lower risk for development of persistent microalbuminuria (HR 0.49 [0.32-0.75], P = 0.0009) and severe nephropathy (0.41 [0.22-0.78], P = 0.006). Our findings in the DCCT/EDIC cohort provide strong evidence that genetic variation at the ACE gene is associated with the development of nephropathy in patients with type 1 diabetes.     

Modulation of the renal response to ACE inhibition by ACE insertion/deletion polymorphism during hyperglycemia in normotensive, normoalbuminuric type 1 diabetic patients

ACE inhibition protects kidney function, but ACE insertion/deletion (I/D) polymorphism affects renal prognosis in type 1 diabetic patients. ACE genotype may influence the renal benefits of ACE inhibition. We studied the impact of ACE I/D polymorphism on the renal hemodynamic changes induced by ACE inhibition in type 1 diabetes. We studied renal hemodynamics (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], filtration fraction [GFR/ERPF], mean arterial pressure [MAP], and total renal resistances [MAP/ERPF]) repeatedly during normoglycemia and then hyperglycemia in 12 normotensive, normoalbuminuric type 1 diabetes and the II genotype (associated with nephroprotection) versus 22 age- and sex-matched subjects with the ACE D allele after three randomly allocated 2- to 6-week periods on placebo, 1.25 mg/day ramipril, and 5 mg/day ramipril in a double-blind, cross-over study. During normoglycemia, the hemodynamic changes induced by ramipril were similar in both genotypes. During hyperglycemia, the changes induced by ramipril were accentuated in the II genotype group and attenuated dose dependently in the D allele group (treatment-genotype interaction P values for ERPF, 0.018; MAP, 0.018; and total renal resistances, 0.055). These results provide a basis to different renal responses to ACE inhibition according to ACE genotype in type 1 diabetes.     

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。     

Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy

Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.     

Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat

Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-beta (TGF-beta) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-beta and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human (CAT-192) anti-TGF-beta monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-beta antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-beta antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition.     

Selenium-deficient diet induces renal oxidative stress and injury via TGF-beta1 in normal and diabetic rats

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of diabetic nephropathy. Although glucose itself can initiate oxidative stress, deficiency of essential trace elements such as selenium (Se) may exacerbate this oxidative stress in diabetic rats. The mechanism by which Se deficiency causes oxidative stress and renal injury is not completely understood. This study tested the hypothesis that Se deficiency induces renal oxidative stress and renal injury via transforming growth factor-beta1 (TGF-beta1). METHODS: Fifty-four male Wistar rats were used. Diabetes was induced in 27 rats by streptozotocin, and the other 27 rats received buffer only. Ten weeks after induction of diabetes, both normal and diabetic rats were killed, their kidneys removed, and glomeruli were isolated. Glomeruli from normal and diabetic rats were incubated in the presence of TGF-beta1 alone or its neutralizing antibody. Antioxidant enzyme (Cu-Zn) superoxide dismutase (Cu-Zn SOD), catalase, and glutathione peroxidase (GSH-Px) activities; total glutathione; and lipid peroxidation were determined. For Se studies, 15 normal and 15 diabetic rats were divided into groups of five each and fed either a regular, Se-deficient, or Se-supplemented diet one week after induction of diabetes. Ten weeks after feeding these diets, rats were killed and glomeruli were isolated. Oxidative stress was examined by determining the mRNA expressions for antioxidant enzymes and also for TGF-beta1. Plasma glucose and albuminuria were determined. Histology of the kidney and interlobular artery was evaluated by light microscopy. RESULTS: In vitro studies showed that TGF-beta1 significantly reduced glomerular catalase and GSH-Px activities as well as total glutathione levels with an increase in lipid peroxidation in both normal and diabetic rats. Antibody to TGF-beta abrogated these changes. There was no effect of TGF-beta1 on Cu-Zn SOD. Like TGF-beta1, a Se-deficient diet caused a significant decrease in glomerular mRNA expression for Cu-Zn SOD, catalase, and GSH-Px, but a significant increase in TGF-beta1 mRNA expression. Also, a Se-deficient diet caused an increase in albuminuria, glomerular sclerosis, and plasma glucose levels in both normal and diabetic rats. The deficient diet caused a decrease in the lumen size of the interlobular artery. Se supplementation to diabetic rats up-regulated mRNA expression for antioxidant enzymes, and significantly reduced but did not normalize that of TGF-beta1. Glomerular sclerosis was normalized and the interlobular artery lumen size was greatly enlarged in diabetic rats by Se supplementation. Also, the tubulointerstitium was preserved by Se supplementation in diabetic rats. CONCLUSIONS: The data show that TGF-beta1 is a pro-oxidant and Se deficiency increases oxidative stress via this growth factor. In addition, Se deficiency may simulate hyperglycemic conditions. Se supplementation to diabetic rats prevents not only oxidative stress but renal structural injury, as well.     

Correlates of ACE activity in macroalbuminuric type 2 diabetic patients treated with chronic ACE inhibition.

The activity of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the development and progression of diabetic nephropathy. However, the effect of angiotensin-converting enzyme (ACE) inhibition on the RAAS appears to be modulated by a number of factors including the I/D polymorphism of the ACE genotype. In this study, we attempted to find independent correlates of ACE activity in 121 macroalbuminuric type 2 diabetic Iranian patients under chronic ACE inhibition. Both univariate and multivariate analyses were used. The presence of the D allele was independently associated with significantly higher levels of ACE activity (with the II genotype as reference, P < 0.001, B = 27.3, 95% CI = 17.6-37.1), and this association was not eliminated by potentially confounding variables. In conclusion, the D allele is a significant independent correlate of ACE activity in macroalbuminuric type 2 diabetic Iranian patients under long-term ACE inhibition.     

ACE DD genotype is more susceptible than ACE II and ID genotypes to the antiproteinuric effect of ACE inhibitors in patients with proteinuric non-insulin-dependent diabetes mellitus.

BACKGROUND: ACE polymorphism, especially genotype DD or D allele, may be involved in the progression of diabetic nephropathy. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. We investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (Benazepril 10 mg/day or Perindopril 4 mg/day) in 83 NIDDM patients with overt proteinuria (urinary protein excretion over 500 mg/day). METHODS: We recruited NIDDM patients with overt proteinuria from our renal clinic. Before entry, previously used ACE inhibitors were withdrawn for at least 2 weeks and baseline proteinuria and albuminuria were measured. Patients were classified into three groups in accordance with ACE genotypes (17 DD; 33 ID; 33 II) and prospectively followed up for 3 months. Various clinical parameters including age, DM duration, body mass index (BMI), 24-h urine sodium, protein and albumin, BUN, serum creatinine, creatinine clearance (Ccr), mean arterial pressure (MAP), and HbA(1c) were measured in the pre- and post-treatment periods. ACE genotypes were determined by polymerase chain reaction. RESULTS: There were no significant differences in the clinical parameters such as age, DM duration, BMI, BUN, serum creatinine, Ccr, MAP, HbA(1c), and daily urinary excretion of sodium, protein and albumin among three groups (P>0.05). After the 3-month treatment period using ACE inhibitors, there were no significant differences in the reduction of MAP and Ccr among the three groups (P>0.05). However, the percentage reductions in urinary excretion of protein and albumin for DD genotype were significantly higher than in ID and II genotypes (50.9+/-19.2% vs 19.2+/-16.0%, 20.2+/-20.4%; 52.6+/-23.6% vs. 13.5+/-51.8%, 24.8+/-23.9%, P<0.05). There were no statistically significant correlations between the levels of baseline proteinuria and albuminuria and the magnitudes of the reduction of proteinuria and albuminuria under ACE inhibition (P>0.05). CONCLUSIONS: Our results suggest that the ACE gene polymorphism might have a role in determining the responsiveness to the antiproteinuric effect of ACE inhibition in proteinuric NIDDM patients.     

Renal angiotensin converting enzyme (ACE) expression in diabetic rats: the effect of ACE inhibitors]

Renal excreted angiotensin converting enzyme (ACE) inhibitor captopril, and renal.hepatic bile excreted ACE inhibitor temocapril, were compared by monitoring serum ACE and renal ACE expression (protein and mRNA) in streptozotocin-induced diabetic rats. Serum ACE levels did not change in untreated diabetic rats or in those treated with temocapril, compared with normal control rats. However, serum ACE levels significantly increased in diabetic rats treated with captopril after 3 months (153.8 +/- 23.0 vs. 43.5 +/- 5.5 IU/l/37 degrees C, p < 0.01) and 6 months (113.6 +/- 9.3 vs. 36.9 +/- 2.9 IU/l/37 degrees C, p < 0.01) compared with normal control rats. Compared with normal control rats (3.6 +/- 0.4), proximal tubular ACE protein expression significantly (p < 0.01) decreased in untreated diabetic rats (1.6 +/- 1.1), but significantly (p < 0.01) increased in diabetic rats treated with captopril (3.7 +/- 0.3) and temocapril (3.5 +/- 0.4). Renal ACE mRNA levels decreased in untreated diabetic rats (125.5 +/- 20.3 vs. 313.3 +/- 53.4, p < 0.01) compared with normal control rats for 6 months. Renal ACE mRNA levels tended to increase in diabetic rats treated with captopril (184.4 +/- 51.2 vs. 125.5 +/- 20.3) and temocapril (165.4 +/- 43.2 vs. 125.5 +/- 20.3) compared with untreated diabetic rats for 6 months. In conclusion, diabetic rats had lower proximal tubular ACE protein expression and lower renal ACE mRNA levels compared with normal control rats. Furthermore, both ACE inhibitors increased renal ACE protein and mRNA expression, but differed in their effect on serum ACE levels.     

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.     

Angiotensin-converting enzyme (ACE) inhibition in type 2, diabetic patients-- interaction with ACE insertion/deletion polymorphism

Angiotensin-converting enzyme (ACE) insertion(I)/deletion (D) polymorphism may modify the effect of inhibition of the renin-angiotensin-aldosterone system (RAAS) on survival and cardiorenal outcomes in type 2, diabetes. A consecutive cohort of 2089 Chinese type 2 diabetic patients with mean (+/- standard deviation) age of 59.7 +/- 13.1 years were genotyped for this polymorphism by polymerase chain reaction method and were followed prospectively for a median period of 44.6 (interquartile range: 23.7, 57.5) months. Clinical outcomes, including all-cause mortality, cardiovascular and renal end points, were examined. The frequency for I allele was 67.1 and 32.9% for D allele, with observed genotype frequencies of 45.8, 42.6, and 11.6% for 3, DI and DD, respectively. ACE DD polymorphism was an independent predictor for renal end point with hazard ratio (HR) (95% confidence interval) of 1.72 (1.16, 2.56), but not for cardiovascular end point or mortality. After controlling for confounding factors, including ACE I/D genotype, the usage of RAAS inhibitors was associated with reduced risk of mortality (HR 0.34 (0.23, 0.50)) and renal end point (HR 0.55 (0.40, 0.75)). On subgroup analysis, the beneficial effects on survival (II vs DI vs DD: HR 0.29 (0.16, 0.51) vs 0.25 (0.14, 0.46) vs 1.33 (0.41, 4.31)) and renoprotection (II vs DI vs DD: 0.52 (0.30, 0.90) vs 0.43 (0.25, 0.72) vs 0.95 (0.43, 2.12)) were most evident in II and DI carriers. In conclusion, inhibition of RAAS was associated with reduced risk of mortality and occurrence of renal end point in Chinese type 2 diabetic patients. These benefits were most evident among II and DI carriers.     

ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy

Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.     

Nonimmunologic complications and gene polymorphisms of immunoregulatory cytokines in long-term renal transplants

BACKGROUND: While the influence of cytokine gene polymorphisms on immunologic complications after organ transplantation is widely evaluated, little is known about predictive value of cytokine genotype for the development of nonimmunologic post-transplant complications: hypertension, dyslipoproteinemia, diabetes mellitus, hyperuricemia. METHODS: The -1082IL-10, -308TNF-alpha, transforming growth factor-beta1 (TGF-beta1) (codon 10, 25), -174IL-6, +874IFN-gamma gene single nucleotide polymorphisms (SNP) were studied in 278 long-term renal transplants by polymerase chain reaction-sequence specific primer (PCR-SSP) with respect to nonimmunologic post-transplant complications. RESULTS: Significant association of the TGF-beta (codon 25) GG genotype with hyperuricemia (P= 0.0013) and dyslipoproteinemia (P= 0.0171) was found. The TGF-beta1 (codon 25) CG genotype was detected more frequently in patients with normal uric acid levels. The +874IFN-gamma AA genotype was associated with type 2/steroid-induced diabetes (P= 0.0127). Frequency of the -1082IL-10 AG genotype was significantly higher in hyperuricemic patients versus controls (P= 0.0022). No associations of polymorphisms in the tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), TGF-beta codon 10 genes with hyperuricemia, dyslipoproteinemia, or diabetes were detected. We failed to observe significant differences in cytokine genotype distribution between hypertensive and normotensive patients. CONCLUSION: We established an association of particular cytokine genotypes with nonimmunologic post-transplant complications. This supports an idea that assessment of cytokine SNPs may allow more accurate prediction of nonimmunologic complications and appropriate adjustment of pre-emptive treatments in long-term transplant patients.     

Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetes patients.

BACKGROUND: Diabetic microvascular complications are the major causes of morbidity and early mortality in diabetes. Vascular endothelial growth factor (VEGF) is a potent multifunctional cytokine which plays a key role in the pathogenesis of diabetic microvascular complications. We examined the possible association of the VEGF gene polymorphisms with diabetic nephropathy and retinopathy in type 2 diabetes patients. METHODS: Genotyping of the VEGF gene insertion/deletion (I/D) and +405 polymorphisms was done by the polymerase chain reaction (PCR) and restriction fragment length polymorphism methods. A total of 426 patients with type 2 diabetes and 493 healthy subjects were genotyped. The frequency of VEGF alleles and genotype distribution were compared in diabetic and control groups. RESULTS: The distribution of the VEGF DD genotype was significantly different in patients with diabetic retinopathy compared with healthy controls, entire diabetic group and patients with no complications (44 vs. 23, 30 and 21%, respectively; P < 0.01). Such differences were not observed in the diabetic nephropathy group. The odds ratio for the D allele was 2.27 (95% CI 1.59-3.25). The multivariate logistic regression analysis revealed that the D allele of the VEGF gene I/D polymorphism was an independent risk factor of retinopathy (P < 0.001). The VEGF +405 genotype was not associated with diabetic complications in type 2 diabetes patients. CONCLUSION: Our study suggests that the I/D polymorphism in the promoter region of the VEGF gene is associated with retinopathy but not nephropathy in type 2 diabetes patients. The multivariate logistic regression analysis showed that the D allele of the VEGF polymorphism is an independent risk factor of diabetic retinopathy after controlling for other clinical variables.     

河北地区汉族人血管紧张素转换酶基因与糖尿病肾病的相关性研究

目的探讨血管紧张素转换酶（ＡＣＥ）基因与糖尿病肾病（ＤＮ）发病的关系。方法用ＰＣＲ方法检测１４９例ＮＩＤＤＭ患者及１００例正常对照的ＡＣＥ基因型。结果（１）ＡＣＥ基因型及等位基因构成比在正常对照组和ＮＩＤＤＭ组间无统计学差异;（２）ＤＤ基因型及Ｄ等位基因频率在ＤＮ组（０２７）显著高于非ＤＮ组（００９）。结论ＡＣＥ基因多态性与ＤＮ发病有关。     

Insertion/deletion polymorphism of the ACE gene is associated with type 2 diabetes

In an attempt to examine the role of an ACE gene insertion/deletion (I/D) polymorphism in type 2 diabetes, we conducted a case-control association study among 132 couple-pairs from northern China. The genotype frequencies for II, ID, and DD were 39.8, 39.8, and 20.3%, respectively, in the case group and 44.8, 44.8, and 10.4% in the control group. The DD frequency was significantly higher in the case group than in the control group (chi(2)(1) = 4.77, P = 0.03), suggesting that the DD genotype is associated with an increased susceptibility to type 2 diabetes in our study population.