T^-786→C Polymorphism of the Endothelial Nitric Oxide Synthase Gene Influences the Progression of Renal Disease

Abstract

Background/Aims: Polymorphism of the endothelial nitric oxide synthase (ecNOS) gene may be involved in renal disease. Recently, T^-786→C polymorphism affecting ecNOS gene transcription has been reported. To clarify the role of T^-786→C polymorphism in renal disease, we investigated hemodialysis patients and healthy controls for this polymorphism and we compared its frequency with that of intron 4 polymorphism in the hemodialysis patients. Methods: The subjects were 252 patients who had been on hemodialysis for less than 2 years (168 with nondiabetic nephropathy and 84 with diabetic nephropathy) and 187 healthy controls. T^-786→C polymorphism was detected using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: The frequencies of the T/C and C/C genotypes were significantly higher in the nondiabetic hemodialysis patients than in the controls (odds ratio 1.41; 95% Cl 1.03–2.00), and were also significantly higher in the diabetic hemodialysis patients than in the controls (odds ratio 1.56; 95% Cl 1.02–2.41). In addition, T^-786→C polymorphism and intron 4 polymorphism showed strong linkage disequilibrium. Conclusion: T^-786→C polymorphism may be involved in the progression of both nondiabetic and diabetic nephropathy, along with intron 4 polymorphism.

T-786C Polymorphism of the Endothelial Nitric Oxide Synthase Gene Is Associated with Albuminuria in the Diabetes Heart Study

“…Our results are consistent with those in two small Japanese and white studies, including a family-based study, which revealed that the Ϫ786C allele influenced the progression of renal disease in nondiabetic, type 1 diabetic, and type 2 diabetic causes of nephropathy (12,18). A positive association between the Ϫ786C variant and CAD was also demonstrated in two other reports (10,21).…”

“…However, variable results have been reported for "a" allele associations with diabetic nephropathy (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The T-786C SNP is strongly linked to the intron 4 polymorphism (18,19), and functional studies reveal that the T-786C mutation reduces NOS3 gene promoter activity (20). Two reports have identified a T-786C association with the presence of CAD (10,21), and two other studies, one family-based, reported that the progression of renal disease was influenced by the T-786C polymorphism (12,18).…”

Genotype-specific Influence on Nitric Oxide Synthase Gene Expression, Protein Concentrations, and Enzyme Activity in Cultured Human Endothelial Cells

“…In persons with the C allele, promoter activity is less than one-half that in those with the T allele. Asakimori et al (27 ) and Ordonez et al (28 ) reported that the T Ϫ786 3 C polymorphism showed strong linkage disequilibrium with the intron 4 VNTR. In the present study, the T Ϫ786 3 C polymorphisms in 43 individuals showed the same allelic distribution as that for the intron 4 VNTR, which means that the C substitution in the T Ϫ786 3 C polymorphism is probably always linked to the presence of the rare 4a allele of the intron 4 VNTR.…”

Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach

“…One of the first indications that genes within chromosome 7q35 (including NOS3) could influence genetic susceptibility to DN came from the nonparametric linkage study in Pima Indians [16]. Several positive associations of some of the numerous NOS3 SNPs with renal disease were documented in type 1 [41] and type 2 diabetes [42], as well as in non-diabetic subjects [43,44], while other studies did not find an association [45]. The two 'set-associated' SNPs in our study-silent substitution 774C/T in exon 6 altering the third base of the codon (both encoding an Asp) and non-synonymous substitution 894G/ T alleles in exon 7 (probably not functional though since the resulting amino acid difference at position 298 Glu to Asp in the oxygenase domain is a conservative one)-are the most probably neutral genetic markers of a yet unidentified functional NOS3 or neighbouring gene polymorphism in a linkage disequilibrium with the two SNPs.…”