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Nephrology 19 (2014) 537–541

Original Article

NOS3 tagSNPs does not modify the chronic kidney disease progression in autosomal dominant polycystic kidney disease GNANASAMBANDAN RAMANATHAN,1 SOUNDARARAJAN PERIYASAMY2 and BHASKAR VKS LAKKAKULA1,3 1

Department of Biomedical Sciences, 2Department of Nephrology, Sri Ramachandra University, Chennai, and 3Sickle Cell Institute Chhattisgarh, Raipur, India

KEY WORDS: chronic kidney disease, genetics, hypertension.

ABSTRACT: Aim: Autosomal dominant polycystic kidney disease (ADPKD) is the most

Correspondence: Dr Bhaskar VKS Lakkakula, Department of Biomedical Sciences, Sri Ramachandra University, No.1 Ramachandra Nagar, Porur, Chennai – 600 116, India. Email: [email protected] Accepted for publication 6 May 2014. Accepted manuscript online 13 May 2014. doi:10.1111/nep.12278 Conflicts of interest The authors have no potential conflict of interests related to the content of this article to declare.

SUMMARY AT A GLANCE The variability in progression to kidney failure in autosomal dominant polycystic kidney disease (ADPKD) could be explained, in part, by single nucleotide polymorphisms (SNPs) in candidate modifier genes. However, the results of the present study provide further evidence that SNPs in the NOS3 gene are not involved in the progression of ADPKD patients.

common hereditary and progressive renal disorder. It is also recognised as the most frequent genetic cause of chronic kidney diseases (CKD). In the present study, four tagging SNPs and two more well studied polymorphisms (Intron 4 VNTR and Glu298Asp) the NOS3 gene were investigated to unravel the potential modifier effect of NOS3 gene on the progression of CKD in ADPKD. Methods: A total of 102 ADPKD patients and 106 controls were selected for the study. The tagSNPs and Glu298Asp polymorphisms were genotyped using FRET-based KASPar method and intron-4 VNTR by polymerase chain reaction electrophoresis. The genotypes and haplotypes in the controls and ADPKD subjects were analysed by χ2 tests and haploview software. MantelHaenszel stratified and univariate analyses were performed to estimate the influence of different genotypes between different CKD stages and hypertension. Results: The tagSNPs of NOS3 genotypes and haplotypes did not exhibit any significant differences between controls and ADPKD patients. The significant linkage disequilibrium was observed between the rs3918184 and rs2853796 by forming LD block. In univariate analysis, the age and family history of Diabetes mellitus (DM) showed significant association with advancement of CKD, but not with the eNOS polymorphisms. Conclusions: Our data suggests that there is no evidence for the involvement of NOS3 tag SNPs in the progression to CKD in ADPKD patients. A systematic study using well validated functional SNPs is necessary to clarify the role of the NOS3 gene in the development of CKD in ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is a frequent genetic cause of chronic kidney disease (CKD) and affects all racial groups worldwide with the prevalence of 1 in 400 to 1000 individuals.1 It is characterized by bilateral cyst formation in the kidneys in an age-dependent manner. This disease is caused by the mutation on either PKD1 or PKD2, which accounts for approximately 85% and 15% of cases, respectively.2 The factors contributing to the variability of severity of renal disease in ADPKD have not been identified so far. However, studies have documented significant interfamilial and intrafamilial phenotype © 2014 Asian Pacific Society of Nephrology

variations in ADPKD3 indicating the involvement of both genetic and environmental factors. Hypertension is one of the most important influencing factors in the progression of ADPKD and was observed approximately in 60% of patients before significant reduction in glomerular filtration rate.4 The release of nitric oxide (NO) by endothelial cells plays an important role in the control of local haemodynamics and systemic blood pressure. Nitric oxide is synthesized by the endothelial NO synthase (eNOS) through the conversion of L-arginine to L-citrulline, using molecular oxygen.5 537

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Several lines of evidence have suggested that the endothelial dysfunction, secondary to an impaired release of NO, exists in ADPKD.6 The human and animal models have also reinforced that the alteration of endothelium-dependent vasodilation is associated with ADPKD.7 In view of the strong association of ADPKD with hypertension, the eNOS enzyme responsible for nitric oxide production, variation in its expression and activity can be linked to hypertension. Hence, the NOS3 gene has long been thought to be a candidate gene for ADPKD. The endothelial NOS gene (NOS3) is composed of 26 exons, spans 21 kb and is located on chromosome 7q35-36. Several single nucleotide polymorphisms have been described in the NOS3 gene and some of them have been associated with altered eNOS function, leading to impaired NO synthesis.8 The Glu298Asp polymorphisms of NOS3 are associated with the level of calcium-dependent NOS activity in vessels8 and lower the vascular activity of eNOS.9 The polymorphisms of the NOS3 gene were found to have significant association with the severity of ADPKD in male patients.8 But no significant association was found between Glu298Asp polymorphism and onset age of ESRD.10 Studies in animal models of PKD have discussed the nature and severity of renal abnormalities associated with specific mutational defects of modifier genes.11 In the present study, four tagging SNPs and two more well studied polymorphisms (Intron 4 VNTR and rs1799983) were investigated to unravel the potential modifier effect of the NOS3 gene on the progression of CKD in ADPKD.

(intron-4 27 bp VNTR and Glu298Asp; rs1799983) were also analyzed in this study. The genotyping of five NOS3 gene polymorphisms was performed by the Fluorescent Resonance Energy Transfer KASPar (FRET) method.16 Genotyping for the intron 4 VNTR was performed using polymerase chain reaction (PCR)-electrophoresis.17

Data analysis The distribution of genotypes was tested for Hardy–Weinberg equilibrium using the χ2 goodness-of-fit test. A χ2 test was carried out to check the association between ADPKD and controls. Measures of pairwise linkage disequilibrium between the studied SNPs were estimated and visualized using Haploview 4.1. Haplotype distributions in control and ADPKD patients were estimated using HaploView 4.1.15 Among the ADPKD patients, univariate logistic regression analysis was performed to determine the effect of genotypes, age, sex, family history of diabetes and hypertension on the progression of CKD. Mantel-Haenszel analysis, χ2 test and calculation of odds ratios (OR) with 95% confidence intervals (CI) were carried out to estimate the influence of different genotypes on the relationship between different CKD stages and hypertension. The SPSS statistical software (version 16.0; SPSS, Chicago, IL, USA), was used to assess the relationship between the genetic variants and P-values 0.8 between haplotypes within LD blocks and haplotypes with minor allele frequency of >5% in the GIH population).15 Two well-studied functional SNPs 538

In the ADPKD group, 48 (47%) of patients (mean age 35.8 ± 6.6 years) showed advanced CKD stage and 54 (53%) of patients (mean age 51.8 ± 4.8 years) showed early CKD stage. In univariate analysis, none of the NOS3 polymorphisms were found to be associated with the development of CKD stage. The age and family history of diabetes mellitus (DM) were significantly associated with the advancement of CKD (Table 2). Only rs1800781 genotypes © 2014 Asian Pacific Society of Nephrology

NOS3 tagSNPs and ADPKD

Table 1 Distribution of NOS3 genotypes in south Indian healthy and autosomal dominant polycystic kidney disease (ADPKD) subjects SNP

rs1800781

VNTR

rs1799983

rs3918184

rs2853796

rs743507

Genotype

Control (n = 106)

ADPKD (n = 102)

OR (95% CI)

P-value*

GG GA AA GA+AA G A MAF HWE-p b/b a/b a/a ab+aa b a MAF HWE-p GG TG TT TG+TT G T MAF HWE-p CC TC TT TC+TT C T MAF HWE-p TT TG GG TG+GG T G MAF HWE-p AA GA GG GA+GG A G MAF HWE-p

84 (79.2) 19 (17.9) 3 (2.8) 22 (20.7) 187 (88.2) 25 (11.2) 11.7 0.154 80 (75.4) 22 (20.7) 4 (3.7) 26 (24.5) 182 (85.8) 30 (14.1) 14.1 0.133 71 (66.9) 28 (26.4) 7 (6.6) 35 (33) 170 (80.2) 42 (19.8) 19.8 0.082 44 (41.5) 52 (49) 10 (9.43) 62 (58.5) 140 (66.0) 72 (34.0) 33.9 0.334 43 (40.5) 42 (39.6) 21 (19.8) 63 (59.4) 128 (60.4) 84 (39.6) 39.6 0.076 79 (74.5) 23 (21.7) 4 (3.7) 27 (25.5) 181 (85.4) 31 (14.6) 14.6 0.177

75 (73.5) 24 (23.5) 3 (2.9) 27 (26.5) 174 (85.3) 30 (14.7) 14.7 0.53 76 (74.5) 24 (23.5) 2 (1.9) 26 (25.5) 176 (86.3) 28 (13.7) 13.7 0.947 73 (71.5) 27 (26.4) 2 (1.96) 29 (28.4) 173 (84.8) 31 (15.2) 15.2 0.784 41 (40.2) 49 (48) 12 (11.7) 61 (59.8) 131 (64.2) 73 (85.8) 35.7 0.647 35 (34.3) 54 (52.9) 13 (12.7) 67 (65.7) 124 (60.8) 80 (39.2) 39.2 0.264 78 (76.4) 23 (22.5) 1 (0.98) 24 (23.5) 179 (87.7) 25 (12.2) 12.2 0.624

Reference 1.42 (0.72–2.79) 1.12 (0.22–5.72) 1.37 (0.72–2.61) Reference 1.28 (0.72–2.27)

0.602 0.331

Reference 1.15 (0.60–2.22) 0.53 (0.09–2.96) 1.05 (0.56–1.97) Reference 0.96 (0.55–1.68)

0.677 0.872

Reference 0.93 (0.50–1.75) 0.28 (0.05–1.38) 0.80 (0.44–1.45) Reference 0.72 (0.43–1.20)

0.253 0.473

Reference 1.01 (0.57–1.80) 1.29 (0.50–2.30) 1.05 (0.60–1.83) Reference 1.08 (0.72–1.62)

0.861 0.847

Reference 1.58 (0.87–2.88) 0.76 (0.33–1.73) 1.30 (0.74–2.29) Reference 0.98 (0.66–1.45)

0.127 0.351

Reference 1.01 (0.53–1.95) 0.25 (0.02–2.32) 0.90 (0.47–1.69) Reference 0.81 (0.46–1.43)

0.421 0.744

0.38

0.9

0.216

0.696

0.479

*χ2 P value; OR, odds ratio; CI, confidence interval; HWp, Hardy-Weinberg p value; MAF, Minor allele frequency.

demonstrated the confounding effect on the relationship between CKD advancement and hypertension by exhibiting the heterogeneity in the effect of hypertension on stages of CKD (homogeneity P = 0.043) (Table 3). © 2014 Asian Pacific Society of Nephrology

Fig. 1 NOS3 gene tagSNP number, variation, and minor allele frequencies are shown in upper portion. In the figure, upper triangles represent D’ values and lower triangles represent r2 values of each box respectively. Bottom, table represents the distribution of NOS3 haplotypes of rs3918184 and rs2853796 between controls and autosomal dominant polycystic kidney disease (ADPKD) patients.

DISCUSSION Analysis of NOS3 tagSNPs did not show any significant association with ADPKD. Linkage disequilibrium was observed to be strong and significant between the rs3918184 and rs2853796 polymorphisms. Haplotypes of these two polymorphisms were not found to be associated with ADPKD. None of the polymorphisms were associated with the advancement of CKD. Only age and family history of diabetes were found to be contributory to the advancement of CKD. Significant heterogeneity was observed in the relationship between the progression of CKD and hypertension for rs1800781 SNP. Hypertension is the most remediable and serious complication of ADPKD. It occurs before the loss of kidney function and influences the progression of CKD in ADPKD.18 A recent study performed with 1139 patients with ADPKD has demonstrated hypertension as the most common clinical manifestation in 76% of cases.19 Several studies have related hypertension with the speed of CKD progression in renal 539

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Table 2 The distribution of NOS3 genotypes among autosomal dominant polycystic kidney disease (ADPKD) subjects and their association with chronic kidney disease (CKD) stages Gene

Genotype

CKD Stages Early Advanced stage stage n = 54 (%) n = 48 (%)

rs1800781

VNTR

Glu298Asp (rs1799983) rs3918184

rs2853796

rs743507

Age

Sex HT FH-DM

GG GA AA b/b a/b a/a GG TG TT CC TC TT TT TG GG AA GA GG 60 F M No Yes No Yes

44 (81.4) 9 (16.6) 1 (1.85) 45 (83.3) 8 (14.8) 1 (1.85) 39 (72.2) 14 (25.9) 1 (1.85) 20 (37.0) 25 (46.3) 9 (16.6) 21 (38.8) 27 (50.0) 6 (11.2) 42 (77.7) 11 (20.3) 1 (1.85) 24 (44.4) 26 (48.1) 4 (7.4) 21 (38.9) 33 (61.1) 12 (22.2) 42 (77.8) 37 (68.5) 17 (31.4)

31 (64.5) 15 (31.2) 2 (4.2) 31 (64.5) 16 (33.3) 1 (2.1) 34 (70.8) 13 (27.1) 1 (2.1) 21 (43.7) 24 (50.0) 3 (6.2) 14 (29.1) 27 (56.2) 7 (14.6) 36 (75.0) 12 (25.0) 0 (0) 9 (18.7) 30 (62.5) 9 (18.7) 24 (50.0) 24 (50.0) 4 (8.3) 44 (91.6) 18 (37.5) 30 (62.5)

Univariate OR (95% CI)

Reference 2.37 (0.92–6.1) 2.84 (0.25–32.70) Reference 2.90 (1.11–7.61) 1.45 (0.09–24.09) Reference 1.07 (0.44–2.58) 1.15 (0.07–19.05) Reference 0.91 (0.40–2.10) 0.32 (0.08–1.34) Reference 1.5 (0.63–3.55) 1.75 (0.49–6.31) Reference 1.27 (0.50–3.23) – Reference 3.08 (1.22–7.79) 6.0 (1.47–24.45) Reference 0.64 (0.29–1.40) Reference 3.14 (0.94–10.52) Reference 3.63 (1.60–8.23)

P-value (χ2)

Gene rs1800781

VNTR

0.154

0.086

0.987

0.259

Glu298Asp (rs1799983)

rs3918184

rs2853796

0.569 rs743507 0.561 0.018 0.012 0.26 0.063 0.002

CI, confidence interval; FH-DM, Family history of diabetes mellitus; HT, Hypertension; OR, odds ratio; VNTR, Variable-number tandem repeats.

disease. The comparison of rapid progression versus slow progression patients has revealed that the rapid progression was associated with a higher incidence of hypertension, haematuria, proteinuria and urinary tract infections.20 Reports have also shown that 70% of ADPKD patients were hypertensives with CKD and cardiovascular complications.21 Better control of blood pressure levels using ACE inhibitors and ARBs has demonstrated a progressive delay in the age at which CKD22 developed and lower mortality rates.23 The animal models as well as clinical studies have revealed the importance of nitric oxide synthase in polycystic kidney disease.24,25 Several studies have also demonstrated the role of NOS3 polymorphisms in nitric oxide production and renal dysfunction in patients with ADPKD. Various polymorphisms such as Glu298Asp (rs1799983), promoter polymorphism (−786T>C) and intron-4 VNTR of NOS3 have been shown to alter eNOS expression, thereby leading to impaired NO synthesis.8,26 The ADPKD patients carrying 4a allele showed delayed progression to ESRD in studies conducted in 540

Table 3 Association between chronic kidney disease (CKD) stages and hypertension stratified by NOS3 genotypes Genotype

OR(95% CI) for HT

P-Value*

GG GA AA M-H Combined b/b a/b a/a M-H Combined GG TG TT M-H Combined CC TC TT M-H Combined TT TG GG M-H Combined AA GA GG M-H Combined

5.44 (1.12–26.37) – – 2.89 (0.836–10.01) 5.27 (1.09–25.55) – – – 1.94 (0.53–7.11 – – 3.08 (0.94–10.13) 3.53 (0.34–37.15) 2.72 (0.612–12.10) – 3.27 (0.94–11.35) 1.88 (0.31–11.37) 7.43 (0.83–66.62) 1.2 (0.06–24.47) 3.0 (0.90–10.05) 1.6 (0.428–5.98) – – 2.76 (0.846–9.03)

0.043

0.062

0.253

0.852

0.514 0.089

*Homogeneity test p value. HT, Hypertension; M-H, Mantel-Haenszel.

Belgium and France, whereas faster ESRD progression was observed in Hellens from Greece and Cyprus.8,27 However, this locus was not associated with the ESRD of different etiologies.27,28 The T allele of the Glu298Asp polymorphism of NOS3 gene is associated with earlier progression to ESRD in ADPKD patients29 and significantly more frequent was observed in rapid progressors when compared to slow progressors.28,30 But in contrast to this the Glu298Asp polymorphism failed to found significant association with renal disease progression in PKD1 population9 and was not associated with the decreasing ESRD age in ADPKD patients.10 However, The Glu298Asp polymorphism of NOS3 gene was associated with lower vascular activity of eNOS.9 No consistent evidence was found with regard to the association between the promoter −786T > C polymorphism and progression to ESRD in type 1 ADPKD patients.8,31 The main strength of this study is the analysis of tagSNPs that covers the majority of known genetic variations in and around the NOS3 gene. The present study has several limitations: plasma nitric oxide levels were not determined and correlated with the progression of CKD as well as NOS3 variants. The sample size used in this study is also a major determinant of statistical power. However, this study revealed that the NOS3 gene tagSNPs were not involved in the progression of CKD in ADPKD. A systematic study using larger sample size and well validated functional SNPs is necessary to clarify the role of the NOS3 gene in the development of CKD in ADPKD. © 2014 Asian Pacific Society of Nephrology

NOS3 tagSNPs and ADPKD

ACKNOWLEDGEMENT This research work was supported by an intramural grant from Sri Ramachandra University, Chennai.

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NOS3 tagSNPs does not modify the chronic kidney disease progression in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary and progressive renal disorder. It is also recognised as the most f...
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