angiotensinogen and Vesico-Ureteral-Reflux

The objective of this study was to investigate whether mutations of the renin-angiotensin system genes are involved in primary vesicoureteric reflux (VUR) and VUR-associated renal scarring. The M235T polymorphism of the angiotensinogen ( ATG) gene, the I/D polymorphism of the angiotensin converting enzyme ( ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor ( AT1) gene were identified in 77 patients with primary VUR (aged 6.9+/-3.2 years, mean+/-SD) and 80 healthy controls (aged 33+/-7 years). Thirty-eight of the 77 VUR patients had low-grade VUR (grade I-III) and 39 had high-grade VUR (grade IV and V). Renal scarring was found in 43 VUR patients, while 34 patients had normal kidneys on dimercaptosuccinic acid scan. The ACE gene polymorphism was determined by polymerase chain reaction and the ATG and AT1 gene polymorphisms were determined by single-step LightCycler technology. We found significant over-representation of the DD genotype in patients with renal scarring (44 %) compared with normal controls (23%, P<0.05) and patients with no scar formation (21%, P<0.05). Significantly higher D and significantly lower I allele frequencies were present in VUR patients with scarred kidneys (D allele 0.64 and I allele 0.36) compared with controls (D allele 0.53 and I allele 0.47, P<0.05) and patients with unscarred kidneys (D allele 0.4 and I allele 0.6, P<0.05). No differences in the ATG and AT1 genotype distributions and allele frequencies were observed in VUR patients compared with the normal population. The DD genotype and D allele of ACE may be a genetic susceptibility factor contributing to scar formation in VUR. We detected no linkage of genetic polymorphisms of ATG and AT1 to VUR and VUR-associated renal scarring.

Topics: Alleles; Angiotensinogen; Child; Female; Genetic Markers; Genotype; Humans; Kidney; Male; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Vesico-Ureteral Reflux

Aim. Renin-angiotensin system (RAS) gene mutations have been implicated as a risk factor for the presence and progression of renal disease in vesicoureteral reflux (VUR). However, the results are contradictory, and the effects of RAS polymorphisms in VUR patients with end-stage renal disease (ESRD) have not been defined yet. This study was designed to evaluate the angiotensin-converting enzyme insertion/deletion (ACE-I/D), angiotensinogen (AGT) M235T, and angiotensin II receptor type 1 (ATR1) A1166C and type 2 (ATR2) C3123A gene polymorphisms as risk factors for progression to ESRD in patients with VUR. Methods. ACE-I/D, AGT-M235T, ATR1-A1166C, and ATR2-C3123A were identified in 161 ESRD patients (52 female, 109 male; 77 renal transplant, 84 dialysis; age: 34.4 +/- 11.2 years). VUR was the ESRD etiology in 40 patients. Genetic polymorphisms of the ACE gene I/D, AGT gene M235T, ATR1 gene A1166C, and ATR2 gene C3123A were identified in all of the patients. Results. We detected no linkage between genetic polymorphisms of ATR1-, ATR2-, AGT-, and VUR-related ESRD. When ACE gene was considered, VUR(+) patients had 63.6% DD, 36.4% ID, and no II alleles, whereas VUR(-) patients had 48.6% DD, 43.2% ID, and 8.1% II alleles. Conclusion. A striking feature of VUR-related ESRD patients was the absence of II alleles, so the DD genotype may be accepted as a genetic susceptibility factor for progression to ESRD in VUR patients.

Topics: Adult; Angiotensinogen; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Disease Progression; Female; Gene Deletion; Gene Frequency; Genetic Predisposition to Disease; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Protein Serine-Threonine Kinases; Renin-Angiotensin System; Risk Assessment; Risk Factors; Vesico-Ureteral Reflux

We studied the angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) gene polymorphisms for association with susceptibility to primary vesicoureteral reflux (VUR) and disease progression in 74 Taiwanese children, including 16 with end-stage renal disease (ESRD), and 117 normal controls. Polymerase chain reaction-amplified products containing the ACE gene T-5491C, A-5466C, T-3892C, A-3692C, A-240T, Alu I/D, the AGT gene C-532T, G-217A, G-152A, A-20C, A-6G, T174M, T235M, and the AT1R gene A-1138T, T-810A, T-713G, C-521T, AG-214CC, A-153G, A1166C polymorphisms were analyzed by restriction enzyme digestion, gel electrophoresis, or single-strand conformation polymorphism analysis. All the polymorphisms examined were in Hardy-Weinberg equilibrium. The strong non-random association within the ACE, AGT, and AT1R genes suggests low levels of intragenic recombination. None of these polymorphisms showed association with VUR susceptibility. However, the allele frequency distribution of the six ACE polymorphisms among primary VUR patients with or without ESRD was statistically different. The linked ACE T-A-T-A-A-I allele was observed significantly more frequently in VUR children with ESRD (P<0.001). A significant increase of left ventricular mass index was also found in the linked ACE T-A-T-A-A-I allele group compared with the non-ACE T-A-T-A-A-I allele group of patients aged 18 years with renal progression. The AGT A-6G genotype frequencies were significantly different when the analysis was stratified by genotype of the ACE polymorphisms. The data showed that ACE gene polymorphisms were associated with progressive renal deterioration in Taiwanese children with VUR and might act synergistically with the -6 G allele of the AGT gene.

Topics: Adolescent; Adult; Angiotensinogen; Child; Disease Progression; DNA Primers; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Kidney Failure, Chronic; Linkage Disequilibrium; Male; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Taiwan; Uremia; Vesico-Ureteral Reflux

Polymorphisms of the renin-angiotensin system (RAS) have been shown to affect renal prognosis in a number of diseases. We examined the influence of deletion (D) and insertion (I) polymorphism in the angiotensin I-converting enzyme (ACE) gene and the other polymorphic markers of RAS, and that of plasminogen-activator inhibitor-1 (PAI-1) on renal scarring in reflux nephropathy. Ninety-four children with third- or fourth-degree reflux were the subject of the study. They were stratified into two groups according to the technetium-99m-dimercaptosuccinic acid (DMSA) findings: the first group consisted of 41 patients with no scar formation. In the second group (n = 53), there was significant scar formation in the refluxing units. ACE levels, ACE gene, angiotensin-1 receptor (AT1) A1166C, angiotensinogen (ATG) M235T, and PAI-1 4G/5G polymorphisms were studied. In the second group with scarred kidneys, 18 patients had decreased renal function. The frequency of patients homozygous for the D allele was significantly greater in the second group with scar formation in the refluxing units compared with the first group of patients (P < 0.005). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 4.9-fold risk (P < 0.05, 95% confidence interval). We were unable to find any correlation with the presence ofDD genotype and hypertension, decreased renal function, proteinuria, or sex of the patient. DDgenotype correlated with the serum ACE levels (P < 0.005). AT1and ATGpolymorphisms and PAI-1 polymorphism did not correlate with scar formation or any of the parameters. This study provides evidence that the DDgenotype of ACE may be a genetic susceptibility factor contributing to adverse renal prognosis in reflux nephropathy; namely, scar formation. The role of the synergism between the aforementioned genetic polymorphisms can be enlightened with larger patient groups, possibly through multicenter studies.

Topics: Angiotensinogen; Case-Control Studies; Child; Child, Preschool; Female; Gene Deletion; Genetic Predisposition to Disease; Genotype; Humans; Kidney; Male; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System; Vesico-Ureteral Reflux