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NDT Advance Access originally published online on December 29, 2005
Nephrology Dialysis Transplantation 2006 21(4):979-983; doi:10.1093/ndt/gfk012
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

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

Monika Buraczynska1,2,*, Piotr Ksiazek1,*, Andrzej Drop3, Wojciech Zaluska2, Danuta Spasiewicz1 and Andrzej Ksiazek2

1 Laboratory for Molecular Diagnostics of Multifactorial Diseases, 2 Department of Nephrology and 3 Department of Radiology, University Medical School, Lublin, Poland

Correspondence and offprint requests to: Monika Buraczynska, Laboratory for Molecular Diagnostics of Multifactorial Diseases, Department of Nephrology, University Medical School, Dr K. Jaczewskiego 8, 20-954 Lublin, Poland. Email: monika.buraczynska{at}am.lublin.pl



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
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.

Keywords: angiotensin-converting enzyme; angiotensinogen; angiotensin II type 1 receptor; DNA polymorphisms; end-stage renal disease



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
The renin-angiotensin system (RAS) has been strongly implicated in the pathogenesis of essential hypertension, cardiovascular disease and progressive renal disease [1–3]. RAS plays a central role in the regulation of blood pressure, sodium metabolism and renal haemodynamics, with its actions mediated primarily by angiotensin II. Angiotensin II is a powerful vasoconstrictor and mediator of cellular proliferation and extracellular matrix protein synthesis and accumulation. Intrarenal effects of the RA system include changes in renal haemodynamics, such as increase in intraglomerular pressure as well as direct stimulation of mesangial cell proliferation and matrix production [4,5].

Association studies based on the comparison of genotype and allele distribution in cases and controls are considered a useful approach in studying the role of candidate genes in the development and progression of multifactorial diseases. Among the candidate genes of the RAS, the angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) genes seem to be particularly biologically and clinically relevant to renal disease. The genetic polymorphisms of these key components of RAS provide a basis for studying the relationship between genetic variants and the development of vascular and/or renal damage in individual subjects [6–8].

ACE gene has a frequent insertion-deletion (I/D) polymorphism characterized by the presence or absence of a 278 bp Alu repetitive sequence in intron 16. This polymorphism is associated with circulating ACE levels [6,9].

Several polymorphisms were identified in the AGT gene which was linked to essential hypertension. Of those, M235T polymorphism (methionine substituted by threonine) was extensively studied in cardiovascular and renal diseases [3].

AT1R polymorphism A1166C is due to a substitution of cytosine for adenine at the position 1166 in 3' untranslated region. It has been considered a risk factor for hypertension and cardiovascular disease [5].

In the present study we examined the association of the ACE, AGT and AT1R gene polymorphisms with the development and progression of end-stage renal disease (ESRD) in a fairly large population of dialysis patients.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients and controls
The study population consisted of 745 unrelated adult individuals on maintenance dialysis (687 haemodialysis and 58 peritoneal dialysis), recruited from ten dialysis centers. All patients were Caucasians of Polish origin. ESRD resulted from chronic glomerulonephritis (n = 246) and interstitial nephritis (n = 121) (both confirmed by renal biopsy in majority of patients) as well as from diabetic nephropathy (n = 141), polycystic kidney disease (n = 69), hypertensive nephropathy (n = 53), obstructive nephropathy (n = 33) and other causes. In about 4% of patients the renal disorder could not be diagnosed adequately.

From the study group, 583 patients (78.2%) were hypertensive and on antihypertensive medication at the start of dialysis. Hypertension was defined as a systolic blood pressure >140 mmHg and a diastolic blood pressure >90 mmHg. Positive family history in first degree relatives was reported by 163 patients (22%). Creatinine, urea, electrolytes, total cholesterol and other standard chemistry evaluations were performed in serum, at the onset of dialysis therapy, according to routine methods. The time interval from the first diagnosis of renal disease to ESRD was assessed by clinicians who did not know the genotype status of the patients.

Healthy control subjects (n = 520), with no clinical signs of vascular or renal disease and no family history of renal disease, were recruited among hospital staff and blood bank donors. An informed consent for genetic studies was obtained from all subjects. The protocol of the study was read and approved by the ethics committee of the University Medical School in Lublin.

Determination of genotypes
Genomic DNA was isolated from all subjects from peripheral blood leukocytes by the standard method.

Angiotensin I-converting enzyme I/D genotype was determined using standard protocol [9]. Because of the preferential amplification of the D allele, each DD genotype was confirmed by using insertion-specific primers [10]. Amplification products had the size of 490 bp for the insertion allele and 190 bp for the deletion allele. With the use of insertion-specific primers, the product of 335 bp was obtained.

Detection of the AGT gene M235T polymorphism was performed by restriction typing of polymerase chain reaction (PCR) product. The following primers were used: forward: 5'-CCGTTTGTGCAGGGCCTGGCTCTCT-3' and reverse: 5'-CAGGGTGCTGTCCACACTGGACCCC-3'. Genomic DNA (300 ng) was amplified in a final volume of 50 µl, containing 10 mM TRIS pH 8.3, 50 mM KCl, 1.5 mM MgCl2, 200 µM each dNTP, 1 µM of each primer and 2 U Taq polymerase (all reagents from MBI Fermentas, St. Leon-Rot, Germany). The initial denaturation at 95°C was followed by 35 cycles of denaturation at 94°C, annealing at 65°C and elongation at 72°C, 1 min each. Final extension was at 72°C for 7 min. The PCR products were digested with PsyI restriction enzyme (MBI Fermentas, St. Leon-Rot, Germany) and DNA fragments were separated by electrophoresis in 2% agarose gel stained with ethidium bromide. The M allele was detected as a band of 165 bp, whereas the mutated T allele showed two fragments, 141 bp and 24 bp.

The A1166C variant of the AT1R gene was identified with primers: forward: 5'-GCAGCACTTCACTACCAAATGGGC-3' and reverse: 5'-CAGGACAAAAGCAGGCTAGGGAGA-3'. The reaction conditions were the same as for the AGT polymorphism, except for the annealing step which was at 55°C. The PCR products were digested with BsuRI restriction enzyme (MBI Fermentas, St. Leon-Rot, Germany). In the presence of cytosine there is a restriction site for this enzyme, resulting in a fragment 231 bp (C allele). Undigested 255 bp fragment indicates the presence of the A allele.

Statistical analysis
Statistical calculations were performed using SPSS for Windows 5.0 (SPSS Inc., Chicago, IL). Hardy–Weinberg equilibrium was tested with the {chi}2 test. Genotype distribution and allele frequencies were compared between groups using a {chi}2 test of independence and z statistics. Odds ratios (OR) with 95% confidence intervals (CI) were estimated for the effects of high risk alleles. Student's t-test was used to compare mean times to ESRD between genotypes. Values of P (two-tailed) <0.05 were considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
We genotyped 745 patients undergoing maintenance dialysis and 520 healthy controls for the ACE, AGT and AT1R gene polymorphisms. The clinical characteristics of both groups are presented in Table 1. The baseline serum creatinine levels and blood pressure values did not differ between genotypes.


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  		Table 1. Clinical characteristics of studied subjects

 
The genotype frequencies in each group satisfied the Hardy–Weinberg equilibrium.

The distribution of genotype and allele frequencies were compared between patients and controls (Table 2). Analysing the entire patient group, no significant difference was observed in the genotype distribution and allele frequencies for the ACE gene polymorphism. The carriers of the T allele of the AGT polymorphism were more frequent in the patient group compared to controls (P = 0.02). The dialysis patient group also showed an increased frequency of the C allele and the homozygous CC genotype of the AT1R polymorphism, compared to controls (0.32 vs 0.20 and 10.3 vs 3%, respectively), OR = 1.87 (95% CI: 1.49 to 2.35). The frequency of combined AC and CC genotypes was also higher in the patient group (53.5 vs 38%, P<0.05). Dialyzed patients with hypertension and those without it showed very similar frequencies of genotypes and alleles of studied polymorphisms (P = 0.08 for ACE, 0.12 for AGT and 0.31 for AT1R).


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  		Table 2. Distribution of alleles and genotypes in dialysis patients and controls

 
Allele frequencies of the examined polymorphisms in the subgroups of patients with most frequent primary renal diseases are presented in Table 3. No statistically significant differences were observed compared to the whole patient group.


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  		Table 3. Allele frequencies in dialysis patients with different primary renal diseases

 
Genetic polymorphisms of the ACE, AGT and AT1R genes were analysed for their association with the rate of progression to ESRD. The results are shown in Figure 1. Progression of renal disease to the end-stage failure in our patient group was influenced by the AT1R polymorphism. We pooled patients homo- and heterozygous for the C allele for comparison with the AA homozygotes. The time from diagnosis to the onset of ESRD was significantly shorter for patients carrying the C allele than for subjects with the homozygous AA genotype (4.7 vs 12.6 years, P<0.001). When progression to ESRD was compared between the AA and AC/CC genotypes in dialysis patients with different primary renal diseases, the highest rate of progression was observed in interstitial nephritis patients with the C allele (4.1 vs 13.3 years for AC + CC subjects). The differences between studied primary diseases were not statistically significant.


Figure 1
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  		Fig. 1. Progression to ESRD in dialyzed patients.

 
No significant differences were found when hypertensive and normotensive patients with AC + CC vs AA genotypes were compared (data not shown).

Some interesting results were obtained when the patient population was divided into late (>50 years of age) and early disease onset subgroups (281 and 464 individuals, respectively). The homozygous TT genotype of the AGT gene polymorphism was more frequent in the late onset subgroup (38 vs 12%, P<0.001). Mean time to ESRD in this subgroup was 3.3 vs 8.7 years for the early onset subgroup (P<0.01).



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Renal disease progression results from the interaction of multiple environmental and genetic factors. Several studies have shown a relationship between genetic variants of the renin-angiotensin system genes and renal diseases as well as the rate of progression of renal damage (reviewed in [3]). There are also studies with negative results concerning these polymorphisms. Therefore, including large numbers of patients from the same population might benefit evaluation of these relationships and add to our knowledge.

We examined the association between the ACE, AGT and AT1R gene polymorphisms and ESRD in dialyzed patients. There are only a few papers published concerning the relationship of these polymorphisms with the rate of progression to ESRD in patients with chronic renal failure resulting from different diseases.

The I/D polymorphism of the ACE gene was studied frequently in cardiovascular and renal diseases. Several reports link this polymorphism to the development and progression of chronic renal diseases of different etiologies [11–14]. Some of these studies, however, involve rather small numbers of patients (n<80). As the association studies are critically dependent on sample size, we included a large group of dialyzed patients in our study. In this group ACE allele frequencies were similar to those described by others for the Polish population. Neither the distribution of ACE genotypes nor the D allele frequency in the entire patient group showed any difference from those in the control group. After dividing a patient population according to underlying renal disease, we still did not observe any differences. This lack of association between the ACE I/D polymorphism and renal failure in our study is in agreement with some reported data, either for the entire ESRD population [15] or the particular primary renal disease [16–18].

Several reports investigated the relationship between the AGT gene M235T polymorphism and development and progression of renal failure in patients with different primary renal diseases. Some reported an association of the T allele of this polymorphism with development of chronic renal disease and renal failure [11,14,19]. There are also contradictory reports, from different populations, that failed to find such association [18,21]. In our study the TT genotype was more frequent in the patient group compared to healthy individuals, but the strong association of the TT genotype of the M235T polymorphism with development of renal failure was observed only in patients with onset of renal disease after 50 years of age. At present this association is difficult to explain and will be a subject of further investigation. The AGT 235T allele is in a linkage disequilibrium with the AGT-6A allele of the promoter region polymorphism which was found to increase the level of transcription of AGT [20]. In a separate study, we genotyped 710 patients from our ESRD group and 490 controls with the AGT G(-6)A polymorphism. The frequency of the A allele was higher in dialyzed patients than the controls (P = 0.04; data not shown). The functional role of the M235T polymorphism, alone or in conjunction with the G(-6)A polymorphism cannot be excluded.

The interesting finding of our study was the association of the AT1R genotype with the development of renal disease and progression to end-stage renal failure. This confirms our previous results [22] with 430 ESRD patients investigated (206 of which, genotyped for all three polymorphisms, were used in the present investigation). We observed a significant difference in the frequency of the C allele and CC homozygotes between patients and controls. Due to a small number of patients with the CC genotype, AC and CC genotypes were pooled for the renal deterioration analysis. Patients carrying the C allele showed more rapid deterioration of renal function than those with the AA genotype. This, to our knowledge, was earlier reported only by us for a dialyzed patient population [22]. In one study, time to ESRD in female patients with diabetic nephropathy who had AC/CC genotype was significantly shorter than in those with the AA genotype [21]. The comparison between hypertensive and normotensive patients indicates that the association of the C allele with renal failure and faster progression to ESRD is independent of hypertension (data not shown).

We are not sure at this point whether the association of the C allele with renal failure progression is dependent on underlying kidney disease. In our previous study [22] the strongest effect was observed in interstitial nephritis. In the present study the highest rate of progression to ESRD was also observed in interstitial nephritis patients with the C allele, but compared to other underlying diseases the differences were not statistically significant. Although we studied a large group of patients, this number is probably still inadequate to assess the role of the C allele in individual disease subgroups.

The risk of renal failure associated with the AT1R C allele seems to be more apparent in dialyzed patients with a positive family history. However, an interactive effect of several factors may lead to an underestimation or an overestimation of the role of any studied polymorphism in determining the phenotype.

The mechanism by which the AT1R A/C polymorphism affects the development of renal disease and its progression to ESRD remains to be elucidated. It is possible that predisposition to renal disease is related to genetic variability in the sensitivity of target tissues to angiotensin II whose actions are mediated by the AT1R receptor. The studied polymorphism is located in the 3' untranslated region of the gene and is apparently a nonfunctional mutation [23]. It may be linked, however, to an unidentified functional mutation in the AT1R gene or in another closely linked gene possibly located in regulatory regions, involved in the development and progression of renal damage.

There are several reports concerning an interaction between RAS gene polymorphisms, affecting the development and progression of cardiovascular and renal disease. Such interactions were observed between the ACE I/D and AGT M235T polymorphisms [14,24], and between ACE I/D and AT1R polymorphisms [1,25]. The relation between AT1R genotype and the progression of ESRD was assessed separately in groups of subjects with different ACE and AGT genotypes. No unfavorable combination of genotypes was found (data not shown).

In conclusion, the present study has failed to confirm any effect of the ACE gene I/D polymorphism on the progression of renal failure in the entire group of dialysis patients, although a fairly large group of ESRD patients was genotyped. We demonstrate the presence of an association between the AGT gene polymorphism (the strongest in patients with late onset of renal disease) and the AT1R A/C polymorphism and renal disease progression. Our results suggest that in patients with chronic renal disease, if confirmed in prospective studies analysing GFR decline over time, the CC/AC genotype might serve as a predictor of an early ESRD. This implies that genotyping for the AT1R gene polymorphism could in the future become an important part of the clinical process of renal risk identification.



   Acknowledgments
 
This study was supported by the University Medical School grant DS 233/02.

Conflict of interest statement. None declared.



   Notes
 
*MB and PK contributed equally to this paper. Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 25. 3.05
Accepted in revised form: 29.11.05


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