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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 552-557
Aldosterone synthase gene is not a major susceptibility gene for progression of chronic kidney disease in patients with autosomal dominant polycystic kidney disease


1 Department of Biomedical Sciences, Sri Ramachandra University, Chennai, Tamil Nadu, India
2 Department of Nephrology, Sri Ramachandra University, Chennai, Tamil Nadu, India
3 Research Division, Sickle Cell Institute Chhattisgarh, Raipur, Chhattisgarh, India

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Date of Web Publication18-May-2017
 

   Abstract 

Autosomal dominant polycystic kidney disease (ADPKD) is the most common heritable kidney disease and is characterized by bilateral renal cysts. Hypertension is a frequent cause of chronic kidney disease (CKD) and mortality in patients with ADPKD. The aldosterone synthase gene polymorphisms of the renin-angiotensin-aldosterone system have been extensively studied as hypertension candidate genes. The present study is aimed to investigate the potential modifier effect of CYP11B2 gene on the progression of CKD in ADPKD. One hundred and two ADPKD patients and 106 healthy controls were recruited based on Ravine inclusion and exclusion criteria. The three tag-SNPs within CYP11B2 gene (rs3802230, rs4543, and rs4544) were genotyped using FRET-based KASPar method. Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Mantel- Haenszel stratified analysis was used to explore confounding and interaction effects of these polymorphisms. Of the three tag-SNPs genotyped, rs4544 polymorphism was monomorphic and rs3802230 deviated Hardy-Weinberg equilibrium. The CYP11B2 tag-SNPs did not show significant association with ADPKD or CKD. Further, these polymorphisms did not exhibit confounding effect on the relationship between CKD progression and hypertension. Our results suggest that aldosterone synthase gene is not a major susceptibility gene for progression of CKD in South Indian ADPKD patients.

How to cite this article:
Ramanathan G, Elumalai R, Periyasamy S, Lakkakula BV. Aldosterone synthase gene is not a major susceptibility gene for progression of chronic kidney disease in patients with autosomal dominant polycystic kidney disease. Saudi J Kidney Dis Transpl 2017;28:552-7

How to cite this URL:
Ramanathan G, Elumalai R, Periyasamy S, Lakkakula BV. Aldosterone synthase gene is not a major susceptibility gene for progression of chronic kidney disease in patients with autosomal dominant polycystic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Jul 16];28:552-7. Available from: http://www.sjkdt.org/text.asp?2017/28/3/552/206464

   Introduction Top


Autosomal dominant polycystic kidney disease (ADPKD) is a late-onset multisystem disorder characterized by bilateral renal cysts that affects an estimated 4–6 million people world- wide.[1] ADPKD is a genetically heterogeneous disorder resulting from mutations of PKD1 and PKD2, which have been proposed to account for 83.3% and 16.7% of cases, respectively.[2] Patients with PKD1 mutations are associated with more severe disease and earlier mean age at the onset of end-stage renal disease (ESRD) than those with mutations in PKD2.[3] ADPKD causes renal and extrarenal manifestations and accounts for approximately 4.7% of cases of ESRD in the United States.[4] Although cyst formation as well as subsequent cyst expansion and growth are the main causes of complications in ADPKD, little is known about the additional environmental and genetic factors that may modify disease severity.[5] Extreme inter- and intra-familial variations in the severity of the phenotype suggest the involvement of modifiers.[6] Modifiable pheno- typic traits such as serum high-density lipo- protein-cholesterol, urine sodium excretion, and 24-h urine osmolality are linked to clinical heterogeneity in ADPKD.[7]

Hypertension occurs approximately in 60–70% of ADPKD individuals and leads to ESRD by 60 years of age.[8] The renin-angiotensin- aldosterone system is the key regulator for the development of hypertension and has been implicated as a mechanism for hypertension. Hypertensive ADPKD patients showed higher serum aldosterone levels compared to the normotensive ADPKD patients.[9] The aldoste- rone synthase (CYP11B2) enzyme plays a key role in the process of aldosterone synthesis in the adrenal glands and its expression is regulated by angiotensin II and potassium.[10] The gene coding for CYP11B2 is located on chromosome 8q22 and contains nine exons. CYP11B2 gene harbors several polymorphic variants that either completely inactivate the encoded CYP11B2 enzyme or significantly impair its synthesis.[11]

There are a few studies assessing the association between CYP11B2 polymorphisms and renal function, which revealed inconsistent and inconclusive results.[12],[13] To our knowledge, no study has analyzed the distribution of CYP11B2 gene polymorphisms and relationships with the progression of chronic kidney disease (CKD) in ADPKD patients. In this study, we investigated the involvement of the CYP11B2 gene polymorphisms on the progression of CKD in ADPKD.


   Materials and Methods Top


Patients

A total of 102 South Indian patients with ADPKD, including 55.88% of men, were recruited from the Department of Nephrology, Sri Ramachandra University, Chennai, between February 2000 and June 2014. The diagnosis of ADPKD was made based on previously described Ravine ultrasound criteria.[14] From the serum creatinine levels of each patient, estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease study formula. Further, among the ADPKD patients, CKD was defined according to the Kidney Disease Outcomes Quality Initiative criteria for stages of CKD, and the patients were divided into two stages such as early stage (CKD stages 1–3) and advanced stage (CKD stages 4 and 5) using eGFR.[15]

After thorough screening, 106 healthy unrelated individuals without family history of polycystic kidney disease or any other kidney- related complications were included as controls. All controls were nondiabetic, normo- tensive, and aged between 30 and 60 years. A written informed consent was obtained from all the participants and it was documented. The study was approved by the Institutional Ethical Committee of Sri Ramachandra University, Chennai, India.

CYP11B2 tag-SNPs (rs3802230, rs4543, and rs4544) were ascertained from genotyped SNPs in a Gujarati Indians in Houston population in the HapMap Project phase II with a minor allele frequency >0.05 and linkage disequilibrium patterns with r[2] >0.8 as a cutoff (www.hapmap.org). We obtained a 3 mL sample of peripheral blood from all the participants, and genomic DNA was isolated according to the standard procedure.[16] The KASPar SNP Genotyping Method (KBioscience, Herts., UK) that uses fluorescent resonance energy transfer (FRET) was adopted for genotyping.[17] Hardy-Weinberg equilibrium was tested for each of the SNPs based on the genotyping of ADPKD patients and healthy controls. Geno- typic associations of SNPs between ADPKD and controls were tested by Cochran-Armitage trend test. Among the ADPKD patients, Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Further, multivariate logistic regression analysis was performed to adjust for the presence of multiple risk factors. Mantel-Haenszel Chi-square test was performed to evaluate the influence of different genotypes on the relationship between different CKD stages and hypertension. All statistical analyses were performed using Statistical Package for the Social Science (SPSS) version 16.0 for Windows (SPSS Inc., Chicago, IL, USA).


   Results Top


Baseline laboratory characteristics of the study participants are documented in [Table 1]. The mean age of the control group was 53.27 ± 12.43 years and of the ADPKD group was 46.89 ± 11.38 years. Of the three tag-SNPs, rs4544 polymorphism was monomorphic and was excluded from further analysis. The genotype frequency data for rs3802230 and rs4543 polymorphisms among controls and the ADPKD group are summarized in [Table 2]. The distribution of CYP11B2 genotypes between the control and ADPKD groups was not statistically significant for both polymorphisms [Table 2]. Among ADPKD patients, 54 individuals (53%) showed early-stage CKD with a mean age of 51.8 ± 4.8 years and 48 patients (47%) showed advanced-stage CKD with a mean age of 35.8 ± 6.6 years. Further, these CYP11B2 genotypes were not significantly different between early- and advanced-stage CKD groups [Table 3]. Both rs3802230 and rs4543 polymorphisms did not exhibit confounding effect on the relationship between CKD progression and hypertension [Table 4].
Table 1: Laboratory characteristics of the study patients and controls.

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Table 2: Distribution of CYP11B2 SNPs in control and autosomal dominant polycystic kidney disease patients.

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Table 3: Distribution of CYP11B2 SNPs in early- and advanced-stage chronic kidney disease.

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Table 4: Association between chronic kidney disease stages and hypertension stratified by CYP11B2 genotypes.

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   Discussion Top


In the present study, we investigated the association between the CYP11B2 tag-SNPs and CKD progression in ADPKD patients. The CYP11B2 tag-SNPs did not show any significant association with ADPKD. None of the polymorphisms were associated with the advancement of CKD in ADPKD patients. Further, these polymorphisms did not exhibit confounding effect on the relationship between CKD progression and hypertension.

Initial studies using clinical and animal models have demonstrated that the excess aldos- terone levels were associated with proteinuria, glomerulosclerosis, and glomerular filtration rate.[18] In corroboration with this, aldosterone receptor blockade remarkably decreased pro- teinuria and retarded the progression to CKD.[19] Increased plasma aldosterone levels were observed in hypertensive ADPKD patients compared with normotensive patients.[9]

Our results are supported by few case-con- trol studies that reported no association between CYP11B2 genotype and renal failure or rate of progression of renal disease in European[12] and Korean populations.[20] Further, no significant association was found between CYP11B2 polymorphism and progression of ESRD caused by IgA nephropathy in Chinese population[21] and diabetes-induced chronic renal insufficiency in Indian population.[22] In contrast to the above findings, CYP11B2 gene polymorphism was associated with the progression of renal dysfunction in female patients with IgA nephro- pathy in the Japanese population.[23] Further, CYP11B2 gene polymorphisms were associated with renal insufficiency in hypertensive patients with renal damage in north-eastern Italian population.[13] However, elevated plasma aldosterone levels have been implicated in the development of hypertension[24],[25] and progression of renal diseases.[26],[27],[28]

The present study has two main limitations. First, the plasma and urine aldosterone levels were not determined to correlate with CKD progression as well as CYP11B2 gene variants. Second, the sample size used in this study is also a major determinant of statistical power. However, our findings do not support the hypothesis that CYP11B2 polymorphism is associated with progression of CKD in patients with ADPKD and suggest that aldos- terone synthase gene is not a major susceptibility gene for progression of CKD in South Indian ADPKD patients. A systematic study using large sample size and well-validated functional SNPs is necessary to clarify the role of the CYP11B2 gene in the development of CKD in ADPKD patients.

Conflict of interest: None declared.

 
   References Top

1.
Wilson PD. Polycystic kidney disease: New understanding in the pathogenesis. Int J Biochem Cell Biol 2004;36:1868-73.  Back to cited text no. 1
[PUBMED]    
2.
Valdenaire O, Rohrbacher E, Mattei MG. Organization of the gene encoding the human endothelin-converting enzyme (ECE-1). J Biol Chem 1995;270:29794-8.  Back to cited text no. 2
[PUBMED]    
3.
Eckardt KU, Alper SL, Antignac C, et al. Autosomal dominant tubulointerstitial kidney disease: Diagnosis, classification, and management - A KDIGO consensus report. Kidney Int 2015;88:676-83.  Back to cited text no. 3
    
4.
Bleyer AJ, Kmoch S. Autosomal dominant tubulointerstitial kidney disease: Of names and genes. Kidney Int 2014;86:459-61.  Back to cited text no. 4
[PUBMED]    
5.
Bleyer AJ, Hart TC. Medullary cystic kidney disease type 2. Am J Kidney Dis 2004;43: 1142.  Back to cited text no. 5
[PUBMED]    
6.
Devuyst O. Variable progression of autosomal dominant polycystic kidney disease: Genetic and molecular counterparts. Nephrol Ther 2006;2 Suppl 2:S104-8.  Back to cited text no. 6
[PUBMED]    
7.
Torres VE, Grantham JJ, Chapman AB, et al. Potentially modifiable factors affecting the progression of autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2011; 6:640-7.  Back to cited text no. 7
[PUBMED]    
8.
Ecder T, Schrier RW. Hypertension in autosomal-dominant polycystic kidney disease: Early occurrence and unique aspects. J Am Soc Nephrol 2001;12:194-200.  Back to cited text no. 8
[PUBMED]    
9.
Schrier RW. Renal volume, renin-angiotensin- aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2009;20:1888-93.  Back to cited text no. 9
[PUBMED]    
10.
Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol 2004;217:67-74.  Back to cited text no. 10
[PUBMED]    
11.
White PC, Rainey WE. Editorial: Polymorphisms in CYP11B genes and 11-hydroxylase activity. J Clin Endocrinol Metab 2005;90: 1252-5.  Back to cited text no. 11
[PUBMED]    
12.
Lovati E, Richard A, Frey BM, Frey FJ, Ferrari P. Genetic polymorphisms of the renin- angiotensin-aldosterone system in end-stage renal disease. Kidney Int 2001;60:46-54.  Back to cited text no. 12
[PUBMED]    
13.
Fabris B, Bortoletto M, Candido R, et al. Genetic polymorphisms of the renin-angio- tensin-aldosterone system and renal insufficiency in essential hypertension. J Hypertens 2005;23:309-16.  Back to cited text no. 13
[PUBMED]    
14.
Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet 1994;343:824-7.  Back to cited text no. 14
[PUBMED]    
15.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39 2 Suppl 1:S1-266.  Back to cited text no. 15
    
16.
Sambrook J, Russell DW. Molecular Cloning: A Laboratory Manual. 3rd ed. New York: Cold Spring Harbor Laboratory Press; 2001.  Back to cited text no. 16
    
17.
Didenko VV. DNA probes using fluorescence resonance energy transfer (FRET): Designs and applications. Biotechniques 2001 ;31:1106- 16, 1118, 1120-1.  Back to cited text no. 17
[PUBMED]    
18.
Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996;98:1063-8.  Back to cited text no. 18
[PUBMED]    
19.
Bianchi S, Bigazzi R, Campese VM. Long- term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 2006;70:2116-23.  Back to cited text no. 19
[PUBMED]    
20.
Lee JE, Bae SY, Kim JY, Pyo HJ; Western Dialysis Physician Association (WDPA), Kwon YJ. Aldosterone synthase gene (CYP11B2) polymorphism in Korean end- stage renal disease patients on hemodialysis. Electrolyte Blood Press 2009;7:67-72.  Back to cited text no. 20
[PUBMED]    
21.
Huang HD, Lin FJ, Li XJ, Wang LR, Jiang GR. Genetic polymorphisms of the renin- angiotensin-aldosterone system in Chinese patients with end-stage renal disease secondary to IgA nephropathy. Chin Med J (Engl) 2010;123:3238-42.  Back to cited text no. 21
[PUBMED]    
22.
Prasad P, Tiwari AK, Kumar KM, et al. Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms. BMC Med Genet 2006;7:42.  Back to cited text no. 22
[PUBMED]    
23.
Song J, Narita I, Goto S, et al. Gender specific association of aldosterone synthase gene polymorphism with renal survival in patients with IgA nephropathy. J Med Genet 2003;40: 372-6.  Back to cited text no. 23
[PUBMED]    
24.
Samavat S, Ahmadpoor P, Samadian F. Aldosterone, hypertension, and beyond. Iran J Kidney Dis 2011;5:71-6.  Back to cited text no. 24
[PUBMED]    
25.
Kang SH, Kim JI, Jeong KH, et al. Clinical characteristics of 159 cases of acute toxic hepatitis. Korean J Hepatol 2008;14:483-92.  Back to cited text no. 25
[PUBMED]    
26.
Arik N, Demirkan F, Erbas B, et al. Acute effect of erythropoietin on plasma renin activity and aldosterone levels in end-stage renal disease. Nephron 1992;60:111.  Back to cited text no. 26
[PUBMED]    
27.
Iitake K, Kimura T, Matsui K, et al. Effect of haemodialysis on plasma ADH levels, plasma renin activity and plasma aldosterone levels in patients with end-stage renal disease. Acta Endocrinol (Copenh) 1985;110:207-13.  Back to cited text no. 27
[PUBMED]    
28.
Woo SJ, Seo JM, Hwang JM. Clinical characteristics of cyclodeviation. Eye (Lond) 2005; 19:873-8.  Back to cited text no. 28
[PUBMED]    

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Correspondence Address:
Bhaskar V. K. S. Lakkakula
Research Division, Sickle Cell Institute Chhattisgarh, Raipur - 492 001, Chhattisgarh
India
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DOI: 10.4103/1319-2442.206464

PMID: 28540892

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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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