title: Study of candidate genes affecting the progression of renal disease in autosomal dominant polycystic kidney disease type 1.
abstract: 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.
authors.affiliation: Hereditary Renal Diseases, Nephrology Department, Fundació Puigvert, Cartagena 340-350, 08025 Barcelona, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Tazón-Vega
authors.forename: Mireia
authors.initials: M
authors.lastname: Vilardell
authors.forename: Laureano
authors.initials: L
authors.lastname: Pérez-Oller
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Xose
authors.initials: X
authors.lastname: Lens
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández-Llama
authors.forename: José
authors.initials: J
authors.lastname: Ballarín
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
mesh_terms: D000328:Adult; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000401:mortality; D011110:Polymorphism, Genetic; D043783:Receptor, Bradykinin B1 / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors