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—to: Rippin JD, Patel A, Belyaev ND, Gill GV, Barnett AH, Bain SC (2003) Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Diabetologia 46:426–428

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To the Editor: In recent years numerous studies have tested associations between various candidate genes and the development or progression of diabetic kidney disease in Type 1 and Type 2 diabetic patients in different populations.

We read with interest the recent paper by Rippin et al. [1], showing the results of a search for associations between molecular markers in the genes encoding for inducible and constitutive endothelial nitric-oxide synthase (iNOS, eNOS) and the presence of overt nephropathy in a large group of Type 1 diabetic patients. The rationale for the study was previous observations linking endothelial dysfunction with cardiovascular disease and diabetic nephropathy, as well as the conflicting results of smaller previous studies on that subject. In the study of Rippin et al. genotype or allele frequencies of both polymorphisms (iNOS +/- and eNOS a/b, a 27-base pairs insertion/deletion in intron 4, which affects plasma nitric oxide concentrations [2]) in patients with overt nephropathy, were not different from those in a normoalbuminuria group. Such an observation, obtained in what appears to be an adequately powered study, practically excludes the role of the polymorphisms examined in the development of nephropathy in Type 1 diabetes.

On the other hand, it has also been documented that hereditary predisposition to progressive renal damage exists, and that such a predisposition is probably independent of underlying causes of kidney disease [3, 4]. Despite a few studies addressing the issue, the molecular basis of this phenomenon is still poorly understood.

While nitric oxide was previously found to be fundamental for the regulation of local renal haemodynamics, diuresis and natriuresis, gene polymorphisms affecting its generation are possible candidates in the search for molecular mechanisms of hereditary predisposition to the development of end-stage renal damage [5, 6].

In 1999 we collected DNA from 247 family trios consisting of patients with chronic renal disease, and both their parents [7]. Of these patients, 157 were receiving dialysis (haemodialysis or peritoneal dialysis), while 90 were being treated conservatively, but had creatinine clearance lower than 30 ml/min. The causes of chronic renal disease were: glomerulonephritis in 120 patients, interstitial nephritis (including chronic pyelonephritis) in 80 patients, and diabetic nephropathy in 47 Type 1 diabetic patients. The subjects of the study gave written informed consent, the study protocol has been approved by the Silesian School of Medicine Ethics Committee and was carried out in accordance with the Declaration of Helsinki.

In 217 of the trios, where good quality DNA was available for the affected patient and both parents, we determined eNOS a/b genotypes. Allele transmission from heterozygous parents to affected offspring was compared using the transmission/disequilibrium test (TDT) [8]. Of 434 parents 125 were heterozygous for the eNOS a/b polymorphism. Transmission of eNOS a/b alleles did not differ significantly from the random transmission of 50%/50% expected if no association exists between the examined marker and phenotype. The numbers of transmitted a/b alleles were 57/68 (46%/54%), (the χ2 value was 0.96, the p value was 0.32) suggesting no association between the examined marker, and the presence of chronic renal failure. The limited number of trios included in our study did not allow us to do further stratification analyses (e.g. by cause of kidney disease). However, allele transmission did not differ from random after stratification by gender (data not shown).

In summary, Rippin et al. observed no association between the eNOS a/b polymorphism and the presence of overt nephropathy in Type 1 diabetic patients in a case-control study. We now present data from a family-based study showing no association between this marker and the development of chronic renal failure in patients with various causes of chronic renal disease. According to our observation, the hypothesis that the eNOS polymorphism represents a molecular mechanism leading to chronic renal failure, independent of causes, is highly unlikely. On the other hand, a minor role of this marker in particular subsets of renal patients with different causes of kidney disease cannot be excluded on the basis of our observations.


  1. 1.

    Rippin JD, Patel A, Belyaev ND, Gill GV, Barnett AH, Bain SC (2003) Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Diabetologia 46:426–428

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    Tsukada T, Yokoyama K, Arai T et al. (1998) Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun 245:190–193

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    Freedman BI, Bowden DW (1995) The role of genetic factors in the development of end-stage renal disease. Curr Opin Nephrol Hypertens 4:230–234

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    Freedman BI, Soucie JM, McClellan WM (1997) Family history of end-stage renal disease among incident dialysis patients. J Am Soc Nephrol 8:1942–1945

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    Tolins J, Palmer RM, Moncada S, Raij L (1990) Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. Am J Physiol 258:H655–H662

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    Treeck B, Aukland K (1997) Effect of L-NAME on glomerular filtration rate in deep and superficial layers of rat kidneys. Am J Physiol 272:F312–F318

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    Zychma MJ, Gumprecht J, Zukowska-Szczechowska E, Grzeszczak W (1999) Polymorphisms in the genes encoding for human kinin receptors and the risk of the end-stage renal failure: results of transmission/disequilibrium test. The End-Stage Renal Diesease Study Group. J Am Soc Nephrol 10:2120–2124

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    Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516

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Correspondence to M. J. Zychma MD PhD.

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Zychma, M.J., Gumprecht, J., Rutkowski, P. et al. —to: Rippin JD, Patel A, Belyaev ND, Gill GV, Barnett AH, Bain SC (2003) Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Diabetologia 46:426–428. Diabetologia 46, 1707–1708 (2003). https://doi.org/10.1007/s00125-003-1230-5

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  • Nitric Oxide
  • Diabetic Nephropathy
  • Chronic Renal Failure
  • Interstitial Nephritis
  • Chronic Renal Disease