Genetic analysis of nitric oxide and endothelin in end-stage renal disease

Background, Genetic factors have been implicated in the development of the common aetiologies of endstage renal disease (ESRD), including renal failur e attributed to hypertension, diabetes mellitus, systemic lupus erythematos us and human immunodeficiency virus infection. Nitric oxide (NO) and endoth elin are powerful vasoactive mediators involved in inflammation and regulat ion of vascular tone and blood pressure. We evaluated the role of the neuro nal constitutive (NOS1) and endothelial constitutive (NOS3) nitric oxide sy nthase genes and the endothelin-1 (EDN-1) gene in predisposition to chronic renal failure in African-Americans. Methods. The study population for the linkage and association analyses in E SRD consisted of 361 individuals from 168 multiplex African-American famili es. These individuals comprised 207 unweighted sibling pairs concordant for all-cause ESRD. Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPH D1-1/2 (EDN-1) were genotyped in the sample. in addition, a mutation, Glu29 8Asp, in exon 7 of NOS3 and a 27 bp variable number tandem repeat (VNTR) ma rker in intron 4 of NOS3 were evaluated in the sibling pairs and in an addi tional 92 unrelated African-Americans with type 2 diabetes mellitus-associa ted ESRD (singletons). Association analyses utilized the relative predispos itional effect method. Model independent linkage analyses were performed us ing GeneHunter-plus and MapMaker/SIBS (exclusion analysis) software. Results. Significant evidence for association with ESRD was detected for al leles 7 and 9 of the NOS1 gene (11.9 and 34.2%, respectively, in unrelated probands of ESRD families versus 6.5 and 27.5%, respectively, in race-match ed controls, both P<0.01). These associations were maintained when the unre lated first sibling from each family was used in a case-control comparison and was most pronounced in the nondiabetic ESRD cases. The NOS3 and EDN-1 m arkers failed to provide consistent evidence for association in the sibling pairs and the diabetic ESRD singletons, although we identified two novel e ndothelial constitutive NOS4 (ecNOS4) VNTR alleles in African-Americans. Si gnificant evidence for linkage was not detected between the NOS genes or th e EDN-1 gene in either all-cause ESRD or when the ESRD sibling pairs were s tratified by aetiology (type 2 diabetic ESRD or non-diabetic aetiologies). Conclusion, Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Amer icans is warranted.