The ENOS polymorphism is not associated with severity of renal disease in polycystic kidney disease 1

Background: The renal phenotype in autosomal dominant polycystic kidney disease (ADPKD) is highly variable. Although genetic and allelic heterogeneity explain part of this variability, significant intrafamilial differences in time to end-stage renal disease (ESRD) indicate that genetic modifiers and the environment influence renal phenotype. Previously, a glutamic acid to aspartic acid polymorphism at residue 298 (E/D298) of the endothelial nitric oxide synthase (eNOS) gene ENOS was associated with disease severity in males with ADPKD. Methods: We typed the E/D298 polymorphism in 215 mutation-defined polycystic kidney disease 1 (PKD1) patients from 80 families. In this population, 96 patients had ESRD, with a median time to renal failure of 53 years. Results: Distribution of ENOS genotypes was 86 (40%), 106 (49.3%), and 23 (10.7%) for EE, ED, and DD, respectively. The occurrence of hypertension was not significantly different between genotypes. Kaplan-Meier renal survival analysis showed no significant difference between genotypes, with a median age to ESRD of 53 years for all genotypes in the total population and 52, 52, and 51 years (men) and 57, 53, and 55 years (women) for DD, DE, and EE, respectively. Conclusion: Although the D298 ENOS allele may be associated with lower vascular activity of ENOS, this did not correlate with severity of renal disease in this PKD1 population. An important difference between this study and one finding a modifying role for ENOS was the rigor in defining the PKD1 population. This study shows the importance of using mutation-characterized populations for association studies in ADPKD.