Human Molecular Genetics, 2002, Vol. 11, No. 3 229-241
© 2002 Oxford University Press
Modifier effect of ENOS in autosomal dominant polycystic kidney disease
Division of Nephrology and 1Division of Endocrine Surgery, and 2Unit of Pharmacology and Therapeutics, Université catholique de Louvain Medical School, Brussels, Belgium, 3Division of Nephrology, KUL Medical School, Leuven, Belgium, 4Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain, 5Division of Nephrology, Hôpital Necker, Paris, France, 6Department of Urology, University of Tokyo, Japan and 7Department of Biology, University of Mons-Hainaut, Mons, Belgium
A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with altered endothelial-dependent vasodilation and decreased vascular production of nitric oxide (NO). Thus, ENOS, the gene coding for the endothelial nitric oxide synthase (eNOS), could have a modifier effect in ADPKD. In order to test this hypothesis, we genotyped 173 unrelated ADPKD patients from Belgium and the north of France for the Glu298Asp, intron 4 VNTR and T-786C polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In males (n = 93), the Glu298Asp polymorphism was associated with a lower age at ESRD (Glu/Asp + Asp/Asp: 49.0 ± 1.2 years, n = 53; Glu/Glu: 53.5 ± 1.5 years, n = 40; simple regression, P = 0.02; multiple regression, P = 0.006). This effect was confirmed in a subset of males linked to PKD1 and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NO synthase (NOS) activity was decreased in renal artery samples from ADPKD males harbouring the Asp298 allele, in association with post-translational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. In conclusion, the frequent Glu298Asp polymorphism of ENOS is associated with a 5 year lower mean age at ESRD in this subset of ADPKD males. This effect could be due to a decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO.
+ To whom correspondence should be addressed. Tel: +32 2 764 18 55; Fax: +32 2 764 54 55; Email: devuyst@nefr.ucl.ac.be
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