G protein beta3 subunit C825T polymorphism in primary IgA nephropathy

BACKGROUND: The T allele of the G protein beta3 subunit (GNB3) C825T polymorphism has been associated with increased signal transduction, increased activity of the kidney Na+/H+ exchanger, and also with late-onset essential hypertension. Hypertension is a strong independent risk factor for progression in IgA nephropathy (IgAN). METHODS: We have studied this polymorphism in a regularly followed cohort of 299 biopsy-proven incident cases of IgAN, collected from 1989 to 1999 [208 males (70%)] and compared the genotypes and alleles distributions to 303 local Caucasian controls matched for the male predominance (214 males). The technique used was a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with BseDI as restriction enzyme and specific primers, followed by gel electrophoresis. RESULTS: The TT, CT, and CC genotype frequencies were 13.7%, 45.8%, and 40.5% in IgAN, respectively, versus 7.6%, 47.2%, and 45.2% in controls, respectively (chi(2)= 6.16; P= 0.05). The excess of TT patients versus non-TT was significant in IgAN versus controls (chi(2)= 5.94; P= 0.015). The T allele frequency was 0.366 in IgAN versus 0.312 in controls (chi(2)= 3.97; P= 0.05). This data indicated that this polymorphism had a significant but mild influence on the occurrence/initiation of IgAN (RR = 1.81; 95% CI 1.07-3.07). In contrast, we could not demonstrate any significant and sustained difference in the clinical presentation and evolution of the homozygous TT patients compared to non-TT patients (CC + CT) despite a mean and median follow-up about 10 years. The progression to arterial hypertension or to chronic renal failure or to end-stage renal failure (ESRF) was not significantly different. In addition, multivariate Cox regression analysis excluded a significant independent role of C825T polymorphism on progression. CONCLUSION: The C825T GNB3 polymorphism had a mild influence on occurrence/initiation of IgAN, but played no significant role in the progression of the disease.     

G-protein beta(3)-subunit C825T genotype and nephropathy in diabetes mellitus.

BACKGROUND: Recent studies have identified a novel polymorphism (C825T) of the gene encoding the beta(3) subunit of heterotrimeric G proteins (G:beta(3)) which is associated with enhanced activation of G-proteins and appears to be more common in hypertensive patients and possibly contributes to decreased kidney allograft survival. METHODS: In the present study we examined the relationship between this genetic variant, type 1 and type 2 diabetes and renal complications of diabetes in 1008 Caucasian patients recruited from an outpatient diabetes clinic and four dialysis centres. We also studied 1940 healthy controls. RESULTS: After multivariate adjustment and in univariate statistics, the G:beta(3) 825TT genotype was not associated with a significantly enhanced risk of diabetes or renal complications. CONCLUSIONS: These findings indicate that the G:beta(3) 825T allele apparently does not contribute to the development of diabetes or associated renal complications in patients with type 1 or type 2 diabetes mellitus.     

GNB3 C825T等位基因多态性与原发性IgA肾病相关性研究

目的：研究G蛋白β3亚基（GNB3）C825T等位基因多态性与原发性IgA肾病（IgAN）的发生与病情进展。方法：病例组为216例原发性IgAN患者,对照组为200例健康志愿者。采用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）技术检测各组GNB3 825位点基因型。病例组分为高血压组与非高血压组;同时按基因型的不同将病例组分为TT组、CT组与CC组。结果：（1）病例组与对照组TT、CT、CC基因型频率分别为21.76%、54.63%、23.61%与18.00%、47.00%、35.00%,两组TT、TC、TT＋TC基因型与CC基因型分布频率存在统计学差异（P〈0.05）;病例组T等位基因分布频率高于对照组（49.07%vs 41.50%,P〈0.05）。（2）216例IgAN中,高血压组与非高血压组TT、CT、CC基因型频率分别为32.88%、49.31%、17.81%与16.09%、57.34%、26.57%（P〈0.05）。高血压组T等位基因频率较非高血压组明显增加（57.53%vs 44.76%,P〈0.05）。（3）病例组不同基因型携带者病理分级轻重无统计学差异（P〉0.05）。（4）病例组中不同基因型携带者在性别、年龄、体重指数、尿蛋白排泄量（〉1 g/d）、血肌酐水平、血胆固醇水平及三酰甘油水平无统计学差异（P〉0.05）,而高尿酸血症的发生存在统计学差异（P〈0.05）,TT组高尿酸血症患者较CT组及CC组高。结论：（1）病例组TT基因型和T等位基因频率较对照组明显增加,结果显示GNB3 825T等位基因可能与IgA肾病的发病有关,提示该基因可能与IgA肾病的遗传易感性相关。（2）GNB3 825T等位基因能影响IgA肾病患者高血压、高尿酸血症的发生。GNB3C825T等位基因多态性与IgA肾病发病及病情进展的相关机制有待进一步研究。     

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.     

G(-699)/C polymorphism in the bradykinin-1 receptor gene in patients with renal failure.

BACKGROUND: Bradykinin is thought to have protective effects on the progression of renal failure. Of particular interest, it has been reported that one polymorphism in the promoter region of the human kinin B1-receptor gene which is associated with higher activity, is less frequently found in patients with end-stage renal failure. The present study was performed to independently confirm these results. DESIGN: Cross-sectional study on 376 healthy controls, 262 non-diabetic dialysis patients and 175 patients with type 1 diabetes >/=10 years and microalbuminuria (of whom 21 were dialysis-dependent) and 334 patients with type 2 diabetes >/=10 years and nephropathy (of whom 61 were dialysis-dependent). METHODS: Genotyping was performed by polymerase chain reaction, followed by restriction enzyme analysis. RESULTS: All groups were in Hardy Weinberg equilibrium. The study showed no significant difference in the frequency of the C-allele between controls (0.093) and non-diabetic dialysis patients (0.095). No significant difference in C-allele frequency was observed between controls and patients with type 1 diabetes and microalbuminuria (0.092) or patients with type 2 diabetes and nephropathy (0.099). CONCLUSION: In large cohorts of patients with non-diabetic end-stage renal disease and diabetic renal disease with and without end-stage renal failure, no change in the frequency of the C-699 allele of the B-1-receptor gene was found.     

G-Protein beta(3) subunit C825T variant, nephropathy and hypertension in patients with type 2 (Non-insulin-dependent) diabetes mellitus

BACKGROUND: There is substantial evidence that hereditary factors contribute to the predisposition to diabetic nephropathy. On the other hand, it has been suggested that genetics of diabetic nephropathy and hypertension may overlap. Recently, a C to T substitution (C825T) in the gene encoding for the guanine-nucleotide-binding protein beta(3) subunit (GNB3) was identified, and this molecular variant was found to be associated with enhanced activation of G proteins and increased risk of the development of hypertension. The aim of the study was to test whether GNB3 C825T polymorphism contributes to the development of incipient or overt nephropathy or hypertension in type 2 diabetic patients. METHODS: GNB3 genotype was determined in 130 type 2 diabetic patients with overt proteinuria or chronic renal failure, 155 diabetic patients with microalbuminuria and 163 control subjects with normoalbuminuria and known type 2 diabetes duration of at least 10 years. RESULTS: No differences in GNB3 genotype distributions or allele frequencies between the study groups were found. Also, no differences between normotensive and hypertensive patients were demonstrated. CONCLUSION: The study provided evidence against the major impact of the GNB3 C825T polymorphism on the increased risk of the development of nephropathy or hypertension in type 2 diabetic patients.     

Relationship of p22phox C242T polymorphism with nephropathy in type 2 diabetic patients

BACKGROUND: In this case-control study, we investigated the possible involvement of the p22phox C242T polymorphism in the development and progression of diabetic nephropathy (DN) in 535 Caucasian Brazilians with type 2 diabetes. We also evaluated the effects of the interaction of the C242T polymorphism with smoking and hypercholesterolemia on the susceptibility to nephropathy. METHODS: Genotype analysis was performed using polymerase chain reaction (PCR) followed by digestion with restriction enzyme. Logistic regression analysis was used to control for independent risk factors associated with nephropathy. RESULTS: The genotype frequencies in patients with overt DN (CC/CT/TT: 0.36/0.47/0.17) were not significantly different from those of diabetic individuals with normoalbuminuria (0.47/0.41/0.12) or microalbuminuria (0.42/0.48/0.10) (p=0.214). Likewise, there were no differences in the T allele frequency among patients with normoalbuminuria, microalbuminuria or overt DN (0.33, 0.34 and 0.40, respectively; p=0.111). However, the T allele was found to be more frequent among smokers with overt nephropathy (macroalbuminuria and/or in dialysis) than those who had normoalbuminuria (43 vs. 32%, p=0.045). The multiple logistic regression analysis confirmed that the CT+TT genotypes were independently associated with a higher risk of having overt nephropathy among smokers [odds ratio (OR)=6.76, 95% confidence interval (95% CI) 1.83-25.02]. CONCLUSIONS: Our study shows a gene-environment interaction associated with the increased risk of DN progression in Caucasian Brazilian smokers with type 2 diabetes. Further studies should be performed to clarify whether it exists, and to what extent there is a relationship between the p22phox C242T polymorphism and DN.     

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.     

血管内皮生长因子基因多态性与糖尿病肾病的相关性研究

目的 探讨血管内皮生长因子(VEGF)-634G／C基因多态性与糖尿病肾病(DN)的关系。方法 运用PCR-限制性多态性片段长度(RFLP)技术检测98例健康对照者和216例2型糖尿病患者[其中DN患者104例，单纯2型糖尿病(DM)患者112例]的基因型，比较各组的基因型和等位基因频率。结果 (1)CC基因型者血清VEGFT水平高于CG及GG型者；(2)DN组CC基因型和C等位基因频率显著高于DM组和正常对照组；(3)与GG型和CG型组相比，CC型组DN的发生率明显上升；(4)Logistic回归分析显示VEGF、VEGF基因多态性、收缩压(SBP)、HbA1c、LDL-C、体重指数(BMI)是DN的危险因素。结论 VEGF-63gG／C多态性与2型DM伴发肾病的发生有关，C等位基因可能是DN的易感基因。     

Underdiagnosis of diabetes mellitus in chronic dialysis patients on the renal transplant waiting list

In diabetic patients long-term patient and graft survival after renal transplantation is reduced compared to nondiabetic graft recipients. Incidence and prevalence of diabetic patients on dialysis is rising continuously; however, there is a surprisingly low prevalence of patients with known diabetes mellitus on our local renal transplant waiting list. In a retrospective study we clarified the underestimation of diabetic dialysis patients on the transplant waiting list. Our local waiting list includes 46 diabetic patients among 377 (12.2%) candidates. Nine patients had type 1 diabetes and 37 type 2 diabetes. Surprisingly, only 20 of 37 patients (ie, 54%) were initially (at the time of wait-listing) classified as (type 2 diabetes mellitus). Primary renal disease in these 17 diabetic patients was classified in only eight patients, whereas the remaining nine were considered as chronic glomerulonephritis (not biopsy-proven and diabetic nephropathy not excluded). We conclude that among uremic patients on the renal transplant waiting list, the prevalence of diabetes mellitus and the number of patients with diabetic nephropathy are notably underdiagnosed.     

Polymorphisms in the B-type natriuretic peptide (BNP) gene are associated with NT-proBNP levels but not with diabetic nephropathy or mortality in type 1 diabetic patients.

BACKGROUND: Circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are elevated in patients with diabetic nephropathy and independently predict excess cardiovascular morbidity and mortality. Therefore, we investigated the association between two polymorphisms -381T/C and 1551G/A of the BNP gene, plasma NT-proBNP levels and mortality prognosis in 380 type 1 diabetic patients with and without diabetic nephropathy. METHODS: In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy {121 men, age [mean (SD)] 41 +/- 9.5 years, duration of diabetes 28 +/- 8.0 years, glomerular filtration rate 67 +/- 28 ml/min/1.73 m2}, and a matched control group of 183 patients with longstanding type 1 diabetes and persistent normoalbuminuria (111 men, age 43 +/- 10.0 years, duration of diabetes 27 +/- 8.3 years) were followed for 12.6 (0.0-12.9) years. Plasma NT-proBNP concentration was determined by immunoassay at baseline. The BNP genotypes were determined by TaqMan chemistry based assays. RESULTS: The two polymorphisms were in almost complete linkage disequilibrium (r2 = 0.883) and thus only the results of the -381T/C promoter polymorphism are shown. There was no significant difference between cases and controls in either genotype distributions (cases TT 32%, TC 53%, CC 15%; controls TT 28%, TC 52%, CC 20%) or allele frequencies (cases T/C 0.58/0.42; controls T/C 0.54/0.46) for the -381T/C polymorphism. Among the 164 normoalbuminuric patients without antihypertensive treatment and previous major cardiovascular disease (CVD), the -381T/C polymorphism was associated with circulating levels of NT-proBNP [median (interquartile range) 21 (5-32), 34 (12-67) and 32 (12-58) ng/l for TT, TC and CC, respectively (P = 0.041)] persisting after adjustment for covariates (P = 0.018). During follow-up, the -381T/C polymorphism did not predict all-cause or cardiovascular mortality among type 1 diabetic patients with or without diabetic nephropathy. CONCLUSIONS: The BNP -381T/C and 1551G/A polymorphisms are associated with circulating levels of NT-proBNP but not with prevalent overt diabetic nephropathy. These polymorphisms do not predict all-cause or cardiovascular mortality in Caucasian type 1 diabetic patients with or without diabetic nephropathy.     

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.      

The 825C/T polymorphism of the G-protein subunit beta3 does not influence blood pressure and renal function in kidney transplant recipients.

BACKGROUND: Recently, a polymorphism at position 825 (C-->T) of the cDNA that encodes the beta3 subunit of heterotrimeric G proteins (Gbeta3) was found to be associated with essential hypertension. The T allele leads to the formation of a truncated splice variant (Gbeta3-s) with enhanced activity, promoting hypertension. We examined whether the T allele had an influence on blood pressure (BP) and early renal function after renal transplantation. METHODS: We determined the Gbeta3 genotype and T allele frequencies in renal transplant patients and examined associations with BP, BP medications, and renal function in the first year after transplantation. RESULTS: In renal transplant recipients (n=216) the frequency of the T allele was marginally increased (0.34 vs 0.29) compared with normal healthy blood donors (n=163). Age, sex and body mass index were similar in patients with the CC, CT and TT genotype. BP, number of BP medications, and serum creatinine levels were also similar for the three genotypes within the first year after transplantation. Significantly more patients with the TT genotype (48%) had glomerulonephritis as the underlying renal disease, compared with the CT (29%) and CC (27%) genotypes. CONCLUSIONS: The T allele of Gbeta3 does not have a negative impact on BP and early renal function in recipients of a renal allograft. The T allele might play a role in the pathogenesis of chronic glomerulonephritides.     

G protein beta 3 subunit 825T allele, hypertension, obesity, and diabetic nephropathy.

The 825T allele of the gene GNB3 which encodes the beta 3 subunit of heterotrimeric G proteins is associated with enhanced signal transduction via G proteins through the generation of a splice variant termed Gbeta3s. It was detected following a classical candidate gene approach using cell lines from patients with enhanced signal transduction and essential hypertension. The high frequency of the 825T allele in 'old' ethnicities, e.g. bushmen and Australian aborigines as well as in black populations, together with its strong association with obesity suggests that the 825T allele is a true 'thrifty genotype'. Development of obesity associated with the 825T allele is strongly influenced by lifestyle, e.g. physical activity, and other exogenous influences like pregnancy. In hypertension the 825T allele is associated with low renin activity and appears to strongly predict the development of left ventricular hypertrophy. In type 2 diabetes the 825T allele was reported to be predispose for end-stage renal disease, whereas this effect has not yet been confirmed for patients with type 1 diabetes.     

Is there additional effect of MTHFR C677T mutation on lipid abnormalities in renal allograft recipients?

BACKGROUND: The MTHFR C677T mutation and elevated atherogenic lipoprotein levels are known as cardiovascular risk factors in patients with renal transplantation treated with cyclosporine (CsA). The aim of the present study was to eveluate the contribution of MTHFR C677T mutation to the risk of dyslipidemia in renal transplant recipients. We also studied the effect of the MTHFR-C677 T genotype on transplant survival. METHODS: The study included 29 nondiabetic renal transplant recipients and 27 healthy controls. MTHFR C677T genotypes were determined by PCR and RFLP techniques. Biochemical parameters were measured in a computerized autoanalyzer. RESULTS: In the patient group, the distribution of the CC, CT, and TT genotypes was 44.8% (n = 13), 37.9% (n = 11), and 17.2% (n = 5), respectively. The frequencies of the C and T alleles were 0.64 and 0.36, respectively. Subjects with the T allele had the highest levels of TC (P <.05) and LDL-C (P <.05); subjects with the CC genotype had the lowest. CONCLUSIONS: We observed that the MTHFR T allele has an unfavorable effect on serum lipid profile, leading to a rise in the total and LDL cholesterol concentrations. Thus, we believe that MTHFR C allele has a protective effect and MTHFR T allele has a detrimental effect on the serum lipid profile.     

Pronatriodilatin gene polymorphisms, microvascular permeability, and diabetic nephropathy in type 1 diabetes mellitus.

Approximately 30% of diabetic patients develop nephropathy, the appearance of which is partially under genetic control. Atrial natriuretic peptide (ANP) has associated physiologic effects on the kidney. This study was conducted to examine the relationship between a newly identified and known polymorphism at the pronatriodilatin (PND) gene locus and renal involvement in type 1 diabetic subjects. Of 454 type 1 diabetic patients (219 men, 235 women), 323 showed no sign of nephropathy, 79 had incipient renal involvement, and 52 established nephropathy; 58 healthy control subjects were examined for comparison. Allele frequencies (C708 versus T708) were: 0.95 and 0.05 in normoalbuminuric patients, respectively; 0.88 and 0.12 in microalbuminuric patients; 0.96 and 0.04 both in those with overt nephropathy and in healthy control subjects (P = 0.011). Patients with incipient nephropathy were in disequilibrium compared with the total diabetic cohort (P = 0.02). In the same populations, an additional genotype for ScaI polymorphism of the PND gene was tested. The A1 and A2 allele frequencies were: 0.21 and 0.79 in normoalbuminuric patients; 0. 13 and 0.87 in microalbuminuric patients; 0.06 and 0.94 in type 1 diabetic subjects with overt nephropathy; and 0.20 and 0.80 in healthy control subjects, respectively (P < 0.0001). A subset of 55 normotensive patients with type 1 diabetes, well matched for clinical features, plasma ANP levels, and microvascular permeability to macromolecules, was investigated on the basis of the C708/T and A2/A1 polymorphisms. Both transcapillary escape rate of albumin (TERalb) and plasma ANP levels were significantly lower in patients with the T708 than with C708 allele, as well as in the A1 than in A2 allele (TERalb: T708 versus C708: 5.5+/-1.7 versus 7.8+/-2.0%/h, P = 0.0001; plasma ANP levels: 8.3+/-3.9 versus 15.3+/-7.7 pg/ml, P = 0.0003; A1 versus A2: 6.05+/-2.2 versus 7.3+/-2.1%/h, P = 0.044; 8.53+/-4.6 versus 14.5+/-7.4 pg/ml, P = 0.0024, respectively). Thus, in a large ethnically homogeneous cohort of diabetic subjects, our data show: (1) a significant association of C708/T polymorphism with microalbuminuria in long-term diabetes and with both lower plasma ANP levels and widespread albumin leakage; and (2) a strong association between ScaI polymorphism and both diabetic nephropathy and plasma ANP concentrations. These results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes.     

No association between a genetic variant of the p22(phox) component of NAD(P)H oxidase and the incidence and progression of IgA nephropathy.

BACKGROUND: The course of glomerulonephritis varies even within the same histological entity, which suggest that genetic factors determine the progression of inflammatory renal diseases. We studied a potential relationship between the C242T gene polymorphism of p22(phox), a subunit of the NAD(P)H oxidase, and frequency as well as progression of immunoglobulin A (IgA) nephropathy. Patients with lupus nephritis were also investigated. The distribution of the C242T gene variation of p22(phox) has not been previously studied in patients with renal disease. METHODS: Patients with IgA nephropathy were from a homogenous ethnic group of patients living in Northern Germany (n=127). Patients with active lupus nephritis WHO classes III/IV (n=46) were also studied. All diagnoses were confirmed by renal biopsy. Healthy blood donors (n=151) exhibited a genotype distribution similar to previously reported values for Caucasians (CC, 41.2%; CT, 45%; TT, 13.8%). However, C242T genotype distribution was not significantly different (chi(2) test) in patients with IgA nephropathy (CC, 44.9%; CT, 48%; TT, 7.1%) or in active lupus nephritis (CC, 54.3%; CT, 34.7%; TT, 11%). Grouping of IgA nephropathy patients as those with mild renal impairment at the time of biopsy (serum creatinine <1.3 mg/dl) and those with more severe renal failure (serum creatinine >1.3 mg/dl) also failed to show a relationship with p22(phox) polymorphism. Log-rank analysis for up to 15 years in selected cases of IgA nephropathy did not show a significant difference in renal survival rate among the three genotypes. CONCLUSIONS: It appears that the C242T polymorphism is not associated with IgA nephropathy or active lupus nephritis and may not affect the progressive deterioration of renal function in patients with IgA nephropathy. However, whether the C242T polymorphism plays a role in other renal diseases remains to be studied.     

Renal replacement therapy for diabetic end-stage renal disease: data from 10 registries in Europe (1991-2000)

BACKGROUND: There is concern about the rising prevalence of type 2 diabetes mellitus and of the resultant nephropathy. This study uses data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry to provide information on the epidemiology and outcome of renal replacement therapy (RRT) for end-stage renal disease (ESRD) due to diabetic nephropathy (DN). METHODS: Data from the following 10 registries: Austria, French-speaking Belgium, Denmark, Finland, Greece, Norway, Scotland (UK), Catalonia (Spain), Sweden, and The Netherlands were combined. Average annual changes (%) were estimated by Poisson regression. Analyses of mortality were performed by Cox regression. RESULTS: An increase in patients with type 2 DN entering RRT has been observed (+11.9% annually, P < 0.05), while large differences in RRT incidence in this disease continue to exist between countries in Europe. There was a reduction in mortality during the first 2 years on dialysis therapy among patients with type 2 DN (AHR 0.96, 95%CI 0.94-0.97 annually). The mortality among transplant recipients decreased for both type 1 DN and nondiabetic ESRD (non DN) within the 1995-1998 cohort (type 1 DN: AHR 0.49, 95% CI 0.35-0.68; non DN: AHR 0.79, 95% CI 0.69-0.90) compared to the 1991-1994 cohort. CONCLUSION: This report has shown that during the last decade there has been a marked increase in the incidence of RRT for type 2 DN. Survival analysis showed that over the period 1991-1999 the mortality rates of all dialysis patients and of type 1 diabetic and nondiabetic renal transplant recipients have fallen.     

CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage renal failure with dialysis

The chemokine (CK) receptor 5 (CCR5) is necessary for two adjacent cysteines (CC)-CKs such as Regulated upon Activation Normal T cell Expressed and Secreted, a/o Macrophage Inflammatory Protein 1alpha/beta to mediate their inflammatory properties. The CCR5 gene polymorphism with 32-basepair deletion (d32) leads to receptor inactivation/dysfunction in homo/heterozygous individuals. We have evaluated its role in both initiation and/or progression of primary immunoglobulin A (IgA) nephropathy (IGAN) in a case-control study involving a prospective cohort of 318 IGAN patients and a matched group of 294 controls. Genotyping was performed by a two-specific primers single polymerase chain reaction technique: normal allele (nl) vs d32 allele. The d32 allele frequency was not different in patients (11.0%) vs controls (8.3%), indicating no significant influence on IGAN initiation. Genotype to clinical phenotype correlation demonstrated that progression to renal/patient death was associated with the d32 allele: 18.2% (12 out of 66 with d32) vs 8.3% (21 out of 252); chi(2)=6.73; P=0.017. The Kaplan-Meier survival without renal/patient death was worse in d32-positive patients (log-rank test; P=0.002). The Cox regression analyses confirmed that the nl/nl genotype was a significant and independent protective factor for progression to end-stage renal failure (ESRF)/dialysis: beta/standard error (s.e.)=-3.1; chi(2)=9.5; relative risk=0.31 (95% confidence interval 0.15-0.65); P=0.002. The d32-CCR5 polymorphism played a significant role in the progression of primary IGAN, with the nl/nl genotype being an independent protective factor for late progression towards ESRF/dialysis. These data raise question about the usefulness of systematic CCR5 genotyping in IGAN patients.     

MTHFR基因多态性与2型糖尿病肾病相关性的研究

目的 研究亚甲基四氢叶酸还原酶（MTHFR）基因多态性与2型糖尿病肾病（DN）易感性的关系.方法 选择111例山西地区汉族人2型糖尿病患者,其中糖尿病肾病（DN＋）组56例,糖尿病非肾病（DN-）组55例,运用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）技术并结合琼脂糖凝胶电泳的方法检测111例患者的MTHFR基因多态性,测定各组间基因型频率和等位基因频率.结果 纯合基因型TT、T等位基因在DN＋组（21.43％,46.43％）的频率均明显高于DN-组（7.27％,29.09％）,差异均具有统计学意义（P＜0.05）.无论是在DN＋组还是DN-组中,TT基因型患者血同型半胱氨酸（Hcy）平均水平均大于CC基因型和CT基因型患者,DN＋组血浆Hcy水平明显高于DN-组,差异均具有统计学意义（P＜0.05）.在叶酸浓度≤6.92nmol/L时,DN＋组（24.24％,48.49％） TT型发生率及T等位基因频率明显高于DN-组（3.70％,25.93％）（P＜0.05）,当叶酸浓度＞6,92nmol/L时,DN＋组TT型发生率及T等位基因频率与DN-组无差异（P＞0.05）.结论 MTHFR基因C677T多态性与糖尿病肾病（DN）发生具有相关性,突变的T等位基因是DN易感基因,但其影响效果受叶酸浓度的影响.