Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases. It is characterized by a substantial variability in the severity of renal phenotype, primarily assessed by the age at end-stage renal disease (ESRD). The role of modifier genes has been shown in various hereditary diseases, including ADPKD. The gene coding for the endothelial nitric oxide synthase (NOS3) is considered to have a modifier effect on the severity of ADPKD, even if there are studies among different populations that have shown contradictory results. In this study, we investigated the influence of one of the most studied polymorphisms of the NOS3 gene, the Glu298Asp polymorphism, on the age at ESRD in ADPKD. We analyzed a total of 100 ADPKD unrelated patients and 107 healthy cohorts from the Greek population. ADPKD patients were classified into two subgroups: patients with early (rapid progressors) and late (slow progressors) age at ESRD. The results suggested that the Glu298Asp polymorphism of NOS3 gene is associated with the onset age of ESRD. The distribution of C/T alleIes is significantly different between rapid and slow ADPKD progressors leading to the conclusion that the T allele of the Glu298Asp polymorphism of NOS3 gene is associated with earlier progression to ESRD in ADPKD patients.

Pirson Y, Chauveau D, Grunfeld JP: Autosomal dominant polycystic kidney disease; in Cameron JS, Davison AM, Grunfeld JP, Kerr DNS, Ritz E (eds): Oxford Textbook of Clinical Nephrology. Oxford, Oxford University Press, 1998, pp 2393–2415.
Ravine D, Walker RG, Gibson RN, Forrest SM, Richards RI, Friend K, Sheffield LJ, Kincaid-Smith P, Danks DM: Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease 1. Lancet 1992;340:1330–1333.
Milutinovic J, Rust RF, Fialcow PH, Agodoa LY, Phillips LH, Rudd TG, Sutherlands S: Intrafamilial phenotypic expression of autosomal dominant polycystic kidney disease. Am J Kidney Dis 1992;19:465–472.
Torra R, Darnell A, Estivill X, Botey A, Revert L: Interfamilial and intrafamilial variability of clinical expression in ADPKD. Contrib Nephrol. Basel, Karger, 1995, vol 115, pp 97–101.
Woo DD, Nguyen DK, Khatibi N, Olsen P: Genetic identification of two major modifier loci of polycystic kidney disease progression in pcy mice. J Clin Invest 1997;100:1934–1940.
Tevfik E, Schrieer RW: Hypertension in autosomal dominant polycystic kidney disease: early occurrence and unique aspects. J Am Soc Nephrol 2001;12:194–200.
Houlston RS, Tomlinson IPM: Modifier genes in humans: strategies for identification. Eur J Hum Genet 1998;6:80–88.
Nadeau JH: Modifier genes in mice and humans. Nat Rev Genet 2001;2:165–174.
Guay-Woodford LM, Wright CJ, Walz G, Churchill GA: Quantitative trait loci modulate renal cystic disease severity in the mouse bpk model. J Am Soc Nephrol 2000;11:1253–1260.
Bihoreau MT, Megel N, Brown JH, Kränzlin B, Crombez L, Tychinskaya Y, Broxholme J, Kratz S, Bergmann V, Hoffman S, Gauguier D, Gretz N: Characterization of a major modifier locus for polycystic kidney disease (Modpkdr1) in the Han:SPRD(cy/+) rat in a region conserved with a mouse modifier locus for Alport syndrome. Hum Mol Genet 2002;11:2165–2173.
Baboolal K, Ravine D, Daniel J, William N, Holmans P, Coles GA, William JD: Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease. Kidney Int 1997;52:607–613.
O’Sullivan DA, Torres VE, Gabow PA, Thibodeau SN, King BF, Bergstralh EJ: Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease. Am J Kidney Dis 1998;32:976–983.
Tolins JP, Palmer RMJ, Moncada S, Raij L: Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. Am J Physiol 1990;258:655–662.
Marsden PA, Heng HHQ, Scherer SW, Stewart RJ, Hall AV, ShiI XM, Tsui LC, Schappert KT: Structure and chromosomal localization of the human constitutive nitric oxide synthase gene. J Biol Chem 1993;268:17478–17488.
Miyahara K, Kawamoto T, Sase K, Yui Y, Toda K, Yang LX, Hattori R, Aoyama T, Yamamoto Y, Doi Y, Ogoshi S, Hashimoto K, Kawai C, Sasayama S, Shizuta Y: Cloning and structural characterization of the human endothelial nitric-oxide-synthase gene. Eur J Biochem 1994;223:719–726.
Nadaud S, Bonnardeaux A, Lathrop M, Soubrier F: Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene. Biochem Biophys Res Commun 1994;98:1027–1033.
Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A, Kawaguchi Y, Hosova T, Igari J: Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in human. Biochem Biophys Res Comm 1998;245:190–193.
Veldman BA, Spiering W, Doevendans PA, Vervoort G, Kroon AA, de Leeuw PW, Smits P: The Glu298Asp polymorphism of the NOS3 gene as a determinant of the baseline production of nitric oxide. J Hypertens 2002;20:2023–2027.
Wang D, Iveren J, Stradgaard S: Endothelium-dependent relaxation of small resistance vessels is impaired in patients with autosomal polycystic kidney disease. J Am Soc Nephrol 2000;11:1371–1376.
Persu A, Stoenoiu MS, Messiaen T, Davila S, Robino C, El-Khattabi O, Mourad M, Horie S, Feron O, Balligand JL, Wattier R, Pirson Y, Chauveau D, Lens XM, Devuyst O: Modifier effect of ENOS in autosomal dominant polycystic kidney disease. Hum Mol Genet 2002;1:229–241.
Reiterova J, Merta M, Tesar V, Stekrova J: Endothelial nitric oxide synthase affects the progression of autosomal dominant polycystic kidney disease. Kidney Blood Press Res 2002;25:87–90.
Lamnissou K, Zirogiannis P, Trygonis S, Demetriou K, Pieridis A, Koptidis M, Deltas CC: Evidence for association of endothelial cell nitric oxide synthase gene polymorphism with earlier progression to end-stage renal disease in a cohort of Hellens from Greece and Cyprus. Genet Test 2004;3:319–324.
Azurmendi P, Fraga A, Muchnik C, Dos Ramos Farias M, Galan F, Guerra D, O’Flaherty M, Arrizurieta E, Martin R: Progression of autosomic dominant polycystic kidney disease: influence of endothelial NO synthase (ecNOS) and renin angiotensin system gene polymorphisms. Medicina 2004;64:139–142.
Reiterova J, Merta M, Stekrova J, Maixnerova D, Obeidova H, Kebrdlova V, Viklicky O, Tesar V: The influence of endothelin-A receptor gene polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy. Folia Biol (Praha) 2007;53:134–137.
Tazon-Vega B, Vilardell M, Perez-Oller L, Ars E, Ruiz P, Devuyst O, Lens X, Fernandez-Llama P, Ballarin J, Torra R: Study of candidate genes affecting the progression of renal disease in autosomal dominant polycystic kidney disease type 1. Nephrol Dial Transplant 2007;22:1567–1577.
Walker D, Consugar M, Slezak J, Rossetti S, Torres V, Christopher W, Harris P: The ENOS polymorphism is not associated with severity of renal disease in polycystic kidney disease 1. Am J Kidney Dis 2003;41:90–94.
Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J: Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 2000;97:2832–2835.
Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 1988;16:1215.
Granath B, Taylor RR, van Bockxmeer FM, Mammote CD: Lack of evidence for association between endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in the Australian Caucasian population. J Cardiovasc Risk 2001;8:235–241.
Testa A, Spoto B, Tripepi G, Mallamaci F, Malatino L, Fatuzzo P, Maas R, Boeger R, Zoccali C: The GLU298ASP variant of nitric oxide synthase interacts with asymmetric dimethyl arginine in determining cardiovascular mortality in patients with end-stage renal disease. J Hypertens 2005;23:1825–1830.
Forte P, Copland M, Smith LM, Milne E, Setherland J, Benjamin N: Basal nitric oxide synthesis in essential hypertension. Lancet 1997;349:837–842.
Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DE: A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat Med 1996;2:41–45.
Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, Haydock S, Hopper RV, Stephens NG, O’Shaughnessy KM, Brown MJ: A common variant of the endothelial nitric oxide synthase (Glu298–>Asp) is a major risk factor for coronary artery disease in the UK. Circulation 1999;100:1515–1520.
Agema WR, De Maat MP, Zwinderman AH, Kastelein JJ, Rabelink TJ, Van Boven AJ, Feskens EJ, Boer JM, Van der Wall EE, Jukema JW: An integrated evaluation of endothelial constitutive nitric oxide synthase polymorphisms and coronary artery disease in men. Clin Sci 2004;107:255–261.
Hibi K, Ishigami T, Tamura K, Mizushima S, Nyui N, Fujita T, Ochiai H, Kosuge M, Watanade Y, Yoshii Y, Kihara M, Kimura K, Ishii M, Umemura S: Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension 1998;32:521–526.
Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M, Kamitani S, Harada M, Ishikawa M, Kuwahara K, Ogawa E, Hamanaka I, Takahashi N, Kaneshige T, Teraoka H, Akamizu T, Azuma N, Yoshimasa Y, Yoshimasa T, Itoh H, Masuda I, Yasue H, Nakao K: Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension 1998;32:3–8.
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