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

Genetic factors have been implicated in the development of the common aetiologies of end-stage renal disease (ESRD), including renal failure attributed to hypertension, diabetes mellitus, systemic lupus erythematosus and human immunodeficiency virus infection. Nitric oxide (NO) and endothelin are powerful vasoactive mediators involved in inflammation and regulation of vascular tone and blood pressure. We evaluated the role of the neuronal constitutive (NOS1) and endothelial constitutive (NOS3) nitric oxide synthase genes and the endothelin-1 (EDN-1) gene in predisposition to chronic renal failure in African-Americans.

The study population for the linkage and association analyses in ESRD consisted of 361 individuals from 168 multiplex African-American families. These individuals comprised 207 unweighted sibling pairs concordant for all-cause ESRD. Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPHD1-1/2 (EDN-1) were genotyped in the sample. In addition, a mutation, Glu298Asp, in exon 7 of NOS3 and a 27 bp variable number tandem repeat (VNTR) marker in intron 4 of NOS3 were evaluated in the sibling pairs and in an additional 92 unrelated African-Americans with type 2 diabetes mellitus-associated ESRD (singletons). Association analyses utilized the relative predispositional effect method. Model independent linkage analyses were performed using GeneHunter-plus and MapMaker/SIBS (exclusion analysis) software.

Significant evidence for association with ESRD was detected for alleles 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-matched controls, both P:<0.01). These associations were maintained when the unrelated first sibling from each family was used in a case-control comparison and was most pronounced in the non-diabetic ESRD cases. The NOS3 and EDN-1 markers failed to provide consistent evidence for association in the sibling pairs and the diabetic ESRD singletons, although we identified two novel endothelial constitutive NOS4 (ecNOS4) VNTR alleles in African-Americans. Significant evidence for linkage was not detected between the NOS genes or the EDN-1 gene in either all-cause ESRD or when the ESRD sibling pairs were stratified by aetiology (type 2 diabetic ESRD or non-diabetic aetiologies).

Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Americans is warranted.