Nephrol Dial Transplant (2001) 16: 185
© 2001 European Renal Association-European Dialysis and Transplant Association
Letters
A polymorphism in the gene for the endothelial nitric oxide synthase and diabetic nephropathy
Department of Internal Medicine, Section of Nephrology, University of Heidelberg, Heidelberg, Germany
Sir,
Endothelial nitric oxide plays a key role in the regulation of blood flow and blood pressure. The gene for the endothelial nitric oxide synthase (ecNOS) is therefore a reasonable candidate gene for diabetic nephropathy (DN) and other renal diseases. A polymorphism in intron 4, consisting of a repetitive sequence of 27bp [1] has been extensively investigated in patients with renal disease, with some studies showing an association [2,3] but others not [4,5].
We examined separately cohorts of Caucasian patients with type 1 and type 2 diabetes with and without diabetic nephropathy (type 1, 194 without DN, 130 with DN; type 2, 217 without and 197 with DN). All patients had a duration of diabetes of at least 10 years and diabetic nephropathy was defined as persistent microalbuminuria (MAE
30 mg/24 h). The polymorphism in intron 4 was analysed by polymerase chain reaction amplification and resulting alleles were separated on agarose gels according to standard protocol as described by Wang et al. [1].
In patients with type 1 diabetics no significant difference in allele frequency or genotype distribution was observed (Table 1
). The same was true when only patients were considered who had a least a duration of 20 years of diabetes or in patients representing the extremes of renal risk (dialysis (n=18) vs normoalbuminuric (n=145); P=0.39 and 0.683 for genotypes and alleles respectively). The same results were observed in patients with type 2 diabetes (Table 1), except for a trend towards a higher frequency of the aa genotype in patients with nephropathy and more than 20 years of duration of diabetes vs patients without nephropathy and more than 20 years of diabetes duration. No association with hypertension, cardiac events, or diabetic retinopathy was found.
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This study does not support the hypothesis that the ecNOS gene plays a role in the development of diabetic nephropathy. One explanation for the discrepancy from previous reports may be ethnicity of the study populations. Most but not all studies published so far examined patients of Japanese origin. Another explanation may be publication of chance findings in cohorts of limited size. Further studies are required in large samples and also in Caucasian populations.
References
- Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DEL. A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nature Med1996; 41–452.
- Neugebauer S, Baba T, Watanabe T. Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes. Diabetes2000; 49: 500–503[Abstract]
- Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram JH, Krolewski AS. Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int2000; 57: 405–413[Web of Science][Medline]
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Wang Y, Kikuchi S, Suzuki H, Nagase S, Koyama A. Endothelial nitric oxide synthase gene polymorphism in intron 4 affects the progression of renal failure in non-diabetic renal disease. Nephrol Dial Transplant1999; 14: 2898–2902
[Abstract/Free Full Text] - Fujita H, Narita T, Meguro H et al. Lack of association between an ecNOS gene polymorphism and diabetic nephropathy in type 2 diabetic patients with proliferative diabetic retinopathy. Horm Metab Res2000; 32: 80–83[Medline]
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