Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with chronic kidney disease

Abstract

Nitric oxide production is reduced in renal disease, partially due to decreased endothelial nitric oxide production. Evidence indicates that nitric oxide deficiency contributes to cardiovascular events and progression of kidney damage. A polymorphism in intron 4 of the endothelial constitutive nitric oxide synthase (ecNOS) gene is a candidate gene in cardiovascular and renal diseases. We investigated a potential involvement of this polymorphism in chronic renal failure. A case-control study involved 78 children with chronic kidney disease (CKD) and 30 healthy controls. All participants were genotyped for the ecNOS4 polymorphism by the polymerase chain reaction (PCR). Dialyzed (maintenance hemodialysis) and conservative treatment children had significantly higher frequency of the aa genotype and ecNOS4a allele (P<0.05) compared with controls. The combined genotype aa+ab vs. bb comparison validated that a allele is a high-risk allele for end-stage renal disease (ESRD) (P<0.05). Serum nitric oxide level was found to be lower in carriers of the ecNOS 4a allele than in noncarriers (100.29±27.32 vs. 152.73±60.39 μmol/l, P=0.04). Interestingly, 85.95% of the ecNOS 4a allele ESRD patients were found hypertensive in comparison to the 60.67% patients of non noncarriers (bb genotype) (P=0.04). Also, 35.90% of the ecNOS 4a allele ESRD patients were found to have cardiovascular disease in comparison to the 5.13% patients of noncarriers (bb genotype) (P=0.01). On multiple linear regression analysis, a allele was independently associated with hypertension (P=0.03). There was a significantly higher frequency of the ecNOS4a allele carriers among CKD children, both on MHD and conservative treatment than in controls. This suggests that the ecNOS gene polymorphism may be associated with an increased risk of chronic renal failure.

Endothelial nitric oxide synthase gene intron 4 variable number tandem repeat polymorphism in β-thalassemia major

“…The present study explored two alleles in intron 4 of the eNOS gene that is reported to be a candidate gene in cardiovascular and renal diseases [23,24]. The larger allele (eNOS4b allele), designated 'b-insertion' has five tandem repeats, and the smaller allele (eNOS4a allele) 'a-deletion' has four repeats [21].…”

“…Determination of endothelial nitric oxide synthase genotypes eNOS genotype was determined using PCR [23,24]. Genomic DNA was extracted from peripheral blood using a QIAamp DNA Blood Mini Kit (Qiagen, GmbH, Hilden, Germany) and was stored at 48C until analysis.…”

“…Several eNOS gene polymorphisms have been reported as 'susceptibility genes' in various human diseases states, including cardiovascular, pulmonary and renal diseases [22][23][24]. The variable number of tandem repeat (VNTR) polymorphism located in intron 4 of eNOS (eNOS4b/a polymorphism) was significantly associated with plasma nitric oxide concentration [25].…”

The role of endothelial nitric oxide synthase gene G894T and intron 4 VNTR polymorphisms in hemodialysis patients with vascular access thrombosis

“…An impairment of nitric oxide production causes abnormalities in vascular function in many diseases including thrombosis, hypertension, atherosclerosis and renal disease (23,24). In the kidney, nitric oxide dilates renal blood vessels and modulates renin secretion.…”

“…In Santos et al (26) study, the VNTR intron 4 a/b polymorphism was not associated with renal disease in Caucasian-Brazilians. Elshamaa et al (23) studied 78 children with chronic kidney disease (CKD) and 30 healthy controls. They showed that an allele was a high-risk allele for ESRD and this data were significantly different (p<0.05).…”