Study of candidate genes affecting the progression of renal disease in autosomal dominant polycystic kidney disease type 1.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder with a wide spectrum of renal involvement. Differences in the age at onset of end-stage renal disease (ESRD) are partially explained by the genetic heterogeneity of the disease but intrafamilial variability remains to be explained. Modifier genes may play a role in disease severity.

Methods: A total of 355 PKD1 patients from 131 families belonging to three different European centres were analysed. According to the age at onset of ESRD patients were classified into two groups: early and late onset. Two different cut-offs were used. Based on literature, early onset was firstly considered when ESRD was reached before 40 years of age and late onset after 60 years of age. Secondly, according to the bimodal distribution of age at onset of ESRD in our population we established two groups with similar variability and the cut-offs were assigned before 48 years of age and after 56 years of age. These groups of patients were then analysed by two different complementary perspectives: (i) using ESRD onset as a quantitative trait when performing survival analysis and Cox regression analysis, and (ii) considering it a qualitative trait. The candidate genes (and polymorphisms) studied were the following: NOS3 (T-786C and E298D), BDKRB1 (-699 G > C), BDKRB2 (R14C), TGFB1 (-509 C > T, R25P and L10P), ACE (I/D), EGFR (IVS1CA) and PKD2 (-9780 G > A, -718 A > G and 83 C > G).

Results: The results disclosed that the ACE polymorphism had a slight influence on the age of onset of ESRD in ADPKD patients and the NOS3 and BDKBR1 polymorphisms showed a very slight involvement in renal outcome.

Conclusions: Our results discard the most prominent functional genes suggested to date, to have a major effect on ADPKD progression in this cohort. Genes strongly implicated in disease severity are yet to be identified. The description of such genes would allow us to establish a prognosis for ADPKD and eventually to develop therapeutic interventions.