Influence of ACE (I/D) and G460W polymorphism of alpha-adducin in autosomal dominant polycystic kidney disease.

BACKGROUND: The deleterious effect of the DD genotype of ACE in autosomal dominant polycystic kidney disease (ADPKD) remains controversial. Small sample size, population admixture and lack of consideration of parameters modulating the effects of ACE genotype, such as gender or alpha-adducin (ADD) genotype, might explain the discrepancy. METHODS: We investigated the effect of ACE (I/D) polymorphism on the age at end-stage renal disease (ESRD) in a homogeneous population of 191 ADPKD patients, according to gender and genotype for the G460W polymorphism of ADD. Cumulative renal survival was assessed in 276 patients from the same families. RESULTS: Though no effect was detected in the whole population, analysis of the male subset (n = 97) showed that patients harbouring the DD genotype of ACE had a 5-year lower mean age at ESRD than DI + II patients [47.8 +/- 1.8 (n = 31) vs 52.8 +/- 1.1 (n = 66), respectively] (P = 0.02). Furthermore, cumulative renal survival was lower in the corresponding pedigrees [47 +/- 1 years, 95% confidence interval (CI) 45-49, vs 51 +/- 1 years, 95% CI 48-54]. The G460W polymorphism of ADD had no effect on the age at ESRD and cumulative renal survival, either alone or in combination with the ACE (I/D) polymorphism. CONCLUSIONS: In this large series of ADPKD patients, we found no effect of the ACE (I/D) polymorphism on the age at ESRD, either alone or in combination with the G460W polymorphism of ADD. However, a deleterious effect of the DD genotype of ACE on renal disease progression was observed in ADPKD males.     

The ACE insertion/deletion polymorphism has no influence on progression of renal function loss in autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) shows a variable clinical course that is not fully explained by the genetic heterogeneity of this disease. We looked for a possible genetic modifier, the ACE I/D polymorphism, and its influence on progression towards end-stage renal failure (ESRF). METHODS: Forty-nine ADPKD patients who reached ESRF <40 years, and 21 PKD1 patients who reached ESRF > 60 years or were not on dialysis at 60 years of age were recruited. Clinical data were provided by questionnaires. Blood was collected for the determination of the ACE insertion/deletion (I/D) polymorphism genotype. The ACE genotype was also determined in a general, control PKD1 group (n=59). RESULTS: Patients who reached ESRF <40 years had significantly more early onset hypertension than patients reaching ESRF >60 years (80% vs 21%; P<0.001). The ACE genotype distribution showed no differences between the groups of the rapid progressors (DD 20%, ID 56%, II 24%), the slow progressors (DD 29%, ID 52%, II 19%) and the general PKD1 control population (DD 31%, ID 47%, II 22%). CONCLUSION: There is no relationship between progression towards ESRD and the ACE I/D polymorphism in ADPKD patients.     

常染色体显性遗传性多囊肾病患者与血管紧张素转换酶基因多态性的关系

目的 研究人常染色体显性遗传性多囊肾病（ADPKD）与血管紧张素转换酶（ACE）基因多态性的关系。 方法 用PCR方法对103例ADPKD患者及16个ADPKD家系（患者35例,非患病直系亲属30人）进行ACE基因多态性分析。收集患者及家系成员的临床资料,以发病年龄、肝囊肿、高血压、尿路感染、尿路结石、血尿等为主要参数,用统计学方法研究该病ACE基因多态性与ADPKD的关系。 结果 DD型患者的发病年龄比DI型患者早7.2岁[（31.90±11.41）岁比（39.10±10.08）岁];DD型患者的发病年龄比Ⅱ型患者[（46.15±14.74）岁]早14.25岁;DI型患者的发病年龄比Ⅱ型患者早7.05岁,各型间的差异均有统计学意义（均P ＜ 0.05）。3组间高血压、血尿差异有统计学意义。11个家系检查结果显示,ACE基因多态性在ADPKD家系中具有遗传连锁关系,但无统计学意义;家系中患病与非患病者ACE基因型频率差异无统计学意义;家系中患病与非患病者男女之间ACE基因型频率差异无统计学意义;家系中肾功能不全组与肾功能正常组之间DD型及D等位基因频率差异有统计学意义（P ＜ 0.05）。 结论 DD型患者的发病年龄较早,Ⅱ型患者的发病年龄较晚,DI型居中。DI型患者血尿的发生率较高,Ⅱ型患者血尿的发生率较低。DI型患者高血压的发生率较高。ACE基因多态性在ADPKD家系中不提供基因诊断信息; ACE基因多态性与人ADPKD的发病无显著相关性;ACE基因多态性与性别无明显关系。DD型基因型是ADPKD发生肾功能不全的易感因素。     

Angiotensin-converting enzyme activity and the ACE Alu polymorphism in autosomal dominant polycystic kidney disease.

BACKGROUND: Previous studies concerning Alu I/D polymorphism in the ACE gene and ADPKD severity have used the Alu genotypes as a representative of the true biological variable, namely ACE activity. However, wide individual and ethnic differences in the proportion of variance in ACE activity explained by the I/D genotype may have confounded these studies. This investigation examines the association between ADPKD severity and ACE in terms of plasma enzyme activity and I/D genotypes in individuals from three different countries. METHODS: Blood samples were collected from 307 ADPKD patients (116 Australian, 124 Bulgarian and 67 Polish) for determination of ACE activity levels and I/D genotypes. Chronic renal failure (CRF) was present in 117 patients and end-stage renal failure (ESRF) in 68 patients. RESULTS: ACE activity was related to the I/D genotype, showing a dosage effect of the D allele (P=0.006). The proportion of variance due to the Alu polymorphism was 14%. No difference in ACE activity and I/D genotype distribution was found between patients with CRF versus normal renal function (P=0.494; P=0.576) or between those with ESRF versus those without ESRF (P=0.872; P=0.825). No effect of the I/D genotype on age at development and progression to renal failure (CRF; ESRF) was detected in the overall group, and in subgroups based on ethnic origin, linkage status and sex. CONCLUSION: ACE is not likely to play a role as a determinant of ADPKD phenotype severity.     

No effect of angiotensin-converting enzyme gene polymorphism on disease progression and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) shows a variable clinical course suggesting that genetic modifiers might play a role. There are conflicting results about the effect of angiotensin-converting enzyme (ACE) gene polymorphism on the progression of renal failure in ADPKD. Also, the association between ACE gene polymorphism and the occurrence of left ventricular hypertrophy (LVH) has not been investigated in patients with ADPKD. METHODS: ACE genotype analysis was performed in 409 Caucasian patients (137 male, 272 female) with ADPKD. Echocardiographic examination was done in 164 of these patients. RESULTS: There were no significant differences between different ACE genotypes regarding renal function, renal volume, urinary protein excretion, blood pressure, the rate of hypertension, the age at diagnosis of hypertension, the rate of LVH and the incidence of end-stage renal disease (ESRD). CONCLUSION: ACE gene polymorphism does not have a significant effect on the development of ESRD and the prevalence of LVH in patients with ADPKD.     

ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies1

ACE genotype and ACE induced renoprotection in chronic proteinuric nephropathies. BACKGROUND: Whether angiotensin-converting enzyme (ACE) gene polymorphism affects disease progression and response to ACE inhibitor therapy in nondiabetic proteinuric nephropathies is not clearly established. METHODS: The relationship between insertion/deletion (I/D) genotypes and proteinuria, rate of glomerular filtration rate decline (DeltaGFR)-centrally evaluated by repeated measures of iohexol plasma clearance-and incidence of end-stage renal disease (ESRD) was prospectively evaluated in 212 patients with nondiabetic proteinuric chronic nephropathies enrolled in the Ramipril Efficacy in Nephropathy (REIN) trial, where patients were randomly assigned to ramipril or conventional treatment. RESULTS: The DeltaGFR +/- SEM (-0.38 +/- 0.09 vs. -0.50 +/- 0.08 vs. -0.36 +/- 0.06 mL/min/1.73 m2 per month) and incidence of ESRD (19 vs. 22 vs. 25%) in the three subgroups with the II, ID, and DD genotypes, respectively, were comparable. Of note, DeltaGFR (-0.28 +/- 0.07 vs. -0.43 +/- 0.09 mL/min/1.73 m2 per month) and incidence of ESRD [14% vs. 36%, P = 0.04, RR (95% CI), 2.62 (1.02 to 6.71)] were lower in ramipril than in conventionally treated patients in the DD genotype, but not in the II and ID genotype. Either at univariate (P = 0.04) or at multivariate (P = 0.01) analysis, ramipril significantly predicted a lower incidence of events in DD, but not in II and ID patients. At three months, ramipril decreased proteinuria more effectively in DD (-38.2%) than in the II (-26.7%) or ID (-19.2%) genotype. In DD (but not in II or ID) ramipril-treated patients, a short-term reduction in proteinuria correlated with DeltaGFR over the entire follow-up period (P = 0.02, r = -0.41). CONCLUSIONS: In nondiabetic proteinuric nephropathies, the ACE I/D polymorphism does not predict disease progression, but is a strong predictor of ACE inhibition-associated renoprotection in that proteinuria, DeltaGFR, and progression to ESRD are effectively reduced in patients with the DD, but not in those with the II or ID genotype.     

Meta-analysis of the relationship between ACE I/D gene polymorphism and end-stage renal disease in patients with diabetic nephropathy

Aims: Diabetic nephropathy (DN) is the major cause for end‐stage renal disease (ESRD) and the pathogenesis for DN developing into ESRD is not clear at present. Results from published studies on the relationship between angiotensin‐converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and ESRD risk in DN patients are still conflicting. This meta‐analysis was performed to evaluate the association between ACE I/D gene polymorphism and ESRD risk in DN patients. Methods: Association studies were identified from the databases of PubMed, Embase and Cochrane Library on 1 October 2011, and eligible investigations were identified and synthesized using the meta‐analysis method. Results were expressed using odds ratios (OR) for dichotomous data and 95% confidence intervals (CI) were also calculated. Results: Twelve studies reporting the relation between ACE I/D gene polymorphism and ESRD risk in DN patients were identified. In overall populations, there was a notable association between D allele or DD genotype and ESRD susceptibility (D: OR = 1.32, 95% CI: 1.11–1.56, P = 0.002; DD: OR = 1.67, 95% CI: 1.25–2.21, P = 0.0004). In the sub‐group analysis according to ethnicity, D allele or DD genotype was associated with ESRD risk in Asians. In Caucasians, the association of DD genotype with ESRD risk was observed, but the D allele was not. Furthermore, ACE I/D gene polymorphism was associated with ESRD risk in patients with DN due to diabetes mellitus type 2, but the association was not found for patients with DN due to diabetes mellitus type‐1. Conclusions: Our results indicate that D allele or DD homozygous is associated with the ESRD susceptibility in DN patients. However, more investigations are required to further this association.     

Angiotensin-converting enzyme genotype and outcome in pediatric IgA nephropathy

Angiotensin-converting enzyme (ACE) I/D polymorphism has been implicated as a genetic marker for progression of glomerular disease. Studies of ACE genotypes in adults with IgA nephropathy (IgAN) have yielded conflicting results. We performed ACE genotyping on 79 patients with IgAN diagnosed prior to age 18 years who had either progressed to end-stage renal disease (ESRD) or are now more than 5 years post biopsy. Mean follow-up was 14.8 years for those with normal renal function. Forty-three (54.4%) subjects had normal renal function and a normal urinalysis at last evaluation. Sixteen (20%) progressed to ESRD and 1 has chronic renal insufficiency. Kaplan-Meier survival curves for progression to ESRD did not differ significantly for the ACE DD, ID, and II genotype groups (P=0.095, log-rank test). By univariate analysis, presence of hypertension and degree of proteinuria at diagnosis, and unfavorable histology but not ACE genotype, was significantly associated with progression to ESRD. In the Cox proportional hazards model that included grade of proteinuria, the ACE D allele was a significant independent predictor of outcome with a hazard ratio of 2.37 (P=0.031). Our data, while inconclusive, suggest that the ACE D allele may associate with poor outcome in pediatric IgAN.     

The angiotensin-converting enzyme genotype and microalbuminuria in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (AD-PKD) has a variable clinical course. Clinical parameters associated with a worse prognosis are hypertension and proteinuria or microalbuminuria (MA). Because chronic stimulation of the renin-angiotensin system is likely to be present in ADPKD patients, the effect of the angiotensin-converting enzyme insertion/deletion (ACE I/D) genotype on the variability of these clinical parameters was examined in untreated ADPKD patients. Proteinuria and MA were determined in 24-h urine collections. BP measurements were performed with an ambulatory monitor, over 24 h. With analysis of covariance, the ACE genotype was found to be significantly associated with MA, corrected for age, gender, GFR, mean arterial pressure, body surface area, and urinary Na+ excretion (P < 0.05). The patients homozygous for the deletion (DD) had the highest rate of MA (P < 0.05) compared to the patients homozygous for the insertion (II). There was no relationship between the ACE genotype and BP or renal function. A significant positive correlation was found between MA and mean arterial pressure (r = 0.31, P < 0.05), whereas a significant negative correlation was found between MA and renal function (r = -0.28, P < 0.05). In conclusion, in ADPKD patients, MA is partly determined by the ACE I/D polymorphism. Because MA is associated with an enhanced progression toward renal failure, the ACE genotype could help in identifying patients at risk for a worse prognosis.     

Polymorphism of the angiotensin-converting enzyme gene in end-stage renal failure patients

The plasma levels of angiotensin-converting enzyme (ACE) are modulated by the insertion (I)/deletion (D) polymorphism within the ACE gene locus. An association between progressive renal disease, raised cardiovascular risk, and ACE plasma levels has been shown. To evaluate the genotype frequencies of the I/D polymorphism in terminal renal failure, we have enrolled 341 dialysis patients (321 on hemodialysis and 20 on peritoneal dialysis) in a district of southern Italy (Foggia). As controls, 1,307 subjects from the same area have been enrolled. Genomic DNA was obtained from leukocytes, and the ACE I/D polymorphism was determined by polymerase chain reaction. Among uremics, 151 subjects (44.3%) carried the DD genotype, 149 (43.7%) the ID, and 41 (12.0%) the II genotype. In controls, 560 subjects (42.8%) had the DD genotype, 577 (44.1%) the ID, and 170 (13.1%) the II genotype (p = n.s.). Among patients, the frequency of DD subjects was higher in men (48.3%) than in women (39. 7%, p < 0.01). A slight different frequency of the DD genotype was found according to the duration of dialysis treatment: 47.5% in patients on dialysis up to 60 months and 41.7 and 40.6% in those with a dialytic age of 60-120 and >120 months, respectively (p for trend: 0.53). Patients with or without cardiovascular diseases, such as hypertension, left ventricular hypertrophy, coronary artery disease, and chronic cardiac failure, did not exhibit any difference in ACE I/D allele and genotype frequencies (p always >0.05). In conclusion, frequencies of the ACE DD genotype were similar in uremics and in controls and did not differ between patients with and without cardiovascular diseases. A nonsignificant inverse relationship with the time spent on dialysis was observed, suggesting that ACE I/D polymorphism may influence the cardiovascular death rate.     

Renin-angiotensin gene polymorphism in children with uremia and essential hypertension

The M235T polymorphism of the angiotensinogen (ANG) gene, the I/D polymorphism of the angiotensin converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor (AT1R) gene were identified in 70 patients with end-stage renal disease [20 pediatric ESRD, aged 14.9+/-3.1, years blood pressure (BP) 139+/-14/91+/-13 mmHg, 50 adult ESRD, aged 48.7+/-18.7 years, BP 149.1+/-24/96.9+/-12 mmHg], 35 with juvenile essential hypertension (JEHT, aged 14.4+/-2.7 years, 24-h mean BP 135.37+/-7.37/72.4+/-7.68 mmHg), 130 adult healthy normotensive controls (aged 34.9+/-8.1 years, BP 117.8+/-8.7/78.7+/-8.5 mmHg), and 20 pediatric controls (aged 13.2+/-1.2 years, BP 109+/-6.5/71+/-5.9 mmHg). The ACE gene polymorphism was determined by polymerase chain reaction and the ANG and AT1R gene polymorphisms by single-step LightCycler technology. The ACE gene distribution of the Hungarian controls did not differ from the results of the other Caucasian populations. In JEHT and pediatric ESRD patients, the MT genotype of ANG was more frequent than in controls (JEHT 80%, pediatric ESRD 74% versus controls 50%, P<0.02). The DD genotype of ACE was over-represented in pediatric ESRD compared with controls (ESRD 45% versus controls 22%, P<0.05). There was a non-significant increase in the CC genotype frequency of AT1R in adult patients with ESRD compared with controls. In conclusion, there was an increased frequency of the ACE DD genotype in pediatric ESRD, which could be a genetic risk factor for the development of ESRD. Furthermore, there was a significant increase in MT genotype frequency of ANG M235T polymorphism in pediatric ESRD and JEHT. The role of AT1R gene polymorphism needs further investigation.     

DD genotype of angiotensin-converting enzyme in type 2 diabetes mellitus with renal disease in Mexican Mestizos

Aim:   The DD genotype of angiotensin-converting enzyme (ACE) has been suggested as a major contributor of diabetic nephropathy in several populations. The purpose of the present study was to determine whether micro/macroalbuminuria is associated with ACE insertion/deletion (I/D) polymorphism in Mexican Mestizos with type 2 diabetes mellitus.
Methods:   A total of 435 patients with type 2 diabetes mellitus, of whom 233 had albuminuria, were characterized for the ACE I/D polymorphism by the polymerase chain reaction method.
Results:   Clinical and biochemical characteristics and frequencies according to DD, ID and II genotypes in patients with and without albuminuria showed no significant differences. However, only females with micro/macroalbuminuria showed higher frequency of a DD genotype than those without albuminuria (27.9%, 21.2% and 10.5%, respectively; P  ≤ 0.044). In addition, female patients with macroalbuminuria without dialysis showed no significant differences with patients undergoing dialysis.
Conclusion:   The ACE DD genotype is a risk factor for the development of renal disease in Mexican Mestizo females with type 2 diabetes, indicating a possible DD genotype-associated sex effect in renal disease.     

Polymorphism of renin-angiotensin system genes in progressive IgA nephropathy

Summary: Clinical studies revealed that angiotensin converting enzyme (ACE) inhibitor reduces proteinuria and attenuates progressive decline in renal function in IgA nephropathy. Recent studies by us and others have demonstrated that the homozygote of the D allele (DD) of the ACE insertion/deletion (I/D) polymorphism is a potential risk factor for poor prognosis in IgA nephropathy, and that this deletion polymorphism predicts the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function in patients with the nephropathy.     

Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is a complex phenotype resulting from underlying kidney diseases of different etiologies as well as from environmental and genetic factors. The responsible genes influencing the development and rate of progression to ESRD have yet to be defined. We examined an association of the three renin-angiotensin system (RAS) gene polymorphisms with renal disease and progression to ESRD in dialyzed patients. METHODS: Genotyping was performed in 745 ESRD patients and 520 control subjects for the angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms using polymerase chain reaction and gel analysis. RESULTS: Allele and genotype frequencies of the ACE polymorphism did not differ significantly between ESRD patients and controls. The patient group showed an increased frequency of the T allele of the AGT polymorphism (P = 0.02) and the C allele and CC genotype of the AT1R polymorphism (P<0.01). There was an association of the AT1R gene polymorphism with the progression of renal disease to end-stage failure. The time from diagnosis to the onset of ESRD was significantly shorter in patients carrying the C allele than in subjects with the homozygous AA genotype (4.7 years vs 12.6 years, P<0.001). The observed effect was not associated with hypertension in studied subjects. CONCLUSION: The results of our study demonstrate the association between the AT1R A/C polymorphism and renal disease progression. The CC/AC genotype of this polymorphism might serve as a predictor for early ESRD and might be useful in planning therapeutic strategies for individual patients.     

Renin-angiotensin system component gene polymorphisms in Japanese maintenance haemodialysis patients

Summary: The renin-angiotension system (RAS) component gene polymorphisms was examined in 216 patients undergoing maintenance haemodialysis (HD) therapy and in 208 control subjects. the RAS polymorphisms selected for analysis were angiotensin I converting enzyme (ACE) I/D, angiotensinogen (Agt) T235/M235, angiotensin II type 1 receptor (AGT1R) A1166/C1166. the control allelic frequencies was ACE I/D (0.63/0.37), Agt T235/M235 (0.16/0.84), and AGT1R A1166/C1166 (0.94/0.06). Recently, relationships between ACE I/D and the progression of renal disease attract great attention in Japanese and Caucasian populations. ACE D allele was expected to be more frequent in HD population. However, no accumulation of ACE D allele or Agt T235 allele, AFT1R C1166 allele in Japanese end-stage renal disease (ESRD) subjects was detected. to explain the paradoxical result of positive association of ACE D allele with progression of renal disease and no bias of ACE genotype in ESRD subjects, further investigation with systematic prospective study regarding the change of ACE genotype distribution around the period of entering dialysis therapy is required.     

Cardiac hypertrophy and remodeling in relation to ACE and angiotensinogen genes genotypes in Chinese dialysis patients

BACKGROUND: Genetic polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes are associated with increased risk of hypertension and left ventricular hypertrophy (LVH) in hypertensive subjects. However, the extent to which these polymorphisms are related to LVH and remodeling in dialysis patients remains unknown. METHODS: Two hundred and forty-six end-stage renal disease (ESRD) patients on peritoneal dialysis and 183 control subjects, all of Chinese origin, were genotyped for the ACE insertion/deletion (I/D) and the AGT M235T gene polymorphisms. Left ventricular mass index (LVMi) and relative wall thickness were measured using echocardiography. RESULTS: Prevalence of ACE DD and AGT TT genotype was 14% and 83%, respectively, in ESRD patients and did not differ significantly from controls. A total percentage of 95% of our patients had LVH (171 with concentric and 63 with eccentric hypertrophy). Adjusting for age, gender, body mass index, duration of dialysis, diabetes, renal diagnosis, hematocrit, systolic and diastolic blood pressure, dialysis urea clearance, residual glomerular filtration rate, and use of converting enzyme inhibitors or angiotensin receptor blockers, AGT TT genotype remained independently associated with greater LVMi (coefficient = 28.73; 95% CI, 5.72 to 51.75; P = 0.015) and relative wall thickness (coefficient = 0.072; 95% CI, 0.022 to 0.122; P = 0.005) than MT/MM genotypes. LVMi and relative wall thickness did not differ significantly among patients with DD, DI, and II genotypes. No statistical significant interaction was noted between ACE and AGT gene polymorphism in relation to LVMi and relative wall thickness. CONCLUSION: Polymorphism of the AGT M235T gene but not ACE I/D gene is associated with greater LVMi and relative wall thickness, indicating more concentric LVH, in Chinese peritoneal dialysis patients. Possible synergistic effects between AGT and ACE gene polymorphism require further evaluation in a larger population.     

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.     

Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism. Gruppo Italiano di Studi Epidemologici in Nefrologia (Gisen)

In the Ramipril Efficacy in Nephropathy study, ramipril decreased the rate of GFR decline (deltaGFR) and progression to end-stage renal disease (ESRD) in 352 patients with proteinuric chronic nephropathies. This study investigated whether in these patients disease outcome and response to treatment were affected by gender or insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. deltaGFR (0.43 +/- 0.05 versus 0.48 +/- 0.08 ml/min per 1.73 m2) and incidence of ESRD (23 and 22%, respectively) were comparable in male and female patients. However, compared to conventional treatment, ramipril decreased deltaGFR (-52% versus -19%) and progression to ESRD (-74% versus -40%) more effectively in women than in men. Thus, the relative risk (95% confidence interval [CI]) of events (ESRD) between conventional and ramipril treatment was 5.52 (1.59 to 19.17, P = 0.003) in women, but only 1.80 (1.08 to 2.97, P = 0.02) in men. This gender-related effect of ramipril was associated with more reduction in proteinuria (-7.8 +/- 4.2% versus -21.9 +/- 5.7%, P = 0.05) and was still evident even after correction for potentially confounding factors such as baseline GFR, daily sodium intake, ramipril dose, BP control, and concomitant treatment with diuretics or dihydropyridinic calcium channel blockers (adjusted RR [95% CI]: women, 5.07 [1.26 to 20.38], P = 0.02; men, 1.44 [0.85 to 2.44], P = 0.17). Ramipril uniformly decreased deltaGFR and incidence of ESRD in women with either DD (-39% and - 100%) or II + ID (-71% and -82%) genotype, and in men (-25% and -50%) with the DD genotype, but had no beneficial effect in men with the II + ID genotype (+18% and +34%). Thus, the relative risk of events (ESRD) between conventional and ramipril-treated men was higher in subjects with the DD genotype (1.85; 0.69 to 4.94) and lower in those with the II +/- ID genotype (0.71; 0.28 to 1.80). Again, in parallel with deltaGFR and events, proteinuria decreased in women with DD (-23.3 +/-8.0%) or II + ID (-16.0 +/- 9.5%) genotype and in men with the DD genotype (-14.8 +/- 7.0%), but did not change in men with II + ID genotype (+ 1.0 +/- 7.8%). Of note, the ACE genotype-related effect of ramipril was still evident even after correction for the above potentially confounding factors (adjusted RR [95% CI]: DD, 2.52 [0.83 to 7.63], P = 0.10; II + ID, 0.35 [0.12 to 1.01], P = 0.05). Thus, among patients with chronic proteinuric nephropathies, men are at increased risk of progression due to their lower response to ACE inhibitor treatment. ACE inhibition is uniformly renoprotective in women regardless of the ACE polymorphism, and in men with the DD genotype, but is virtually devoid of beneficial effects in men with the II or ID genotype. This information may help to guide therapeutic interventions in clinical practice and to interpret the results of prospective trials in chronic renal disease.     

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。