Genetic variation of DKK3 may modify renal disease severity in ADPKD.
Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/beta-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.
Liu
Michelle
M
Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Shi
Sally
S
Senthilnathan
Sean
S
Yu
Julie
J
Wu
Elliot
E
Bergmann
Carsten
C
Zerres
Klaus
K
Bogdanova
Nadja
N
Coto
Eliecer
E
Deltas
Constantinos
C
Pierides
Alkis
A
Demetriou
Kyproula
K
Devuyst
Olivier
O
Gitomer
Berenice
B
Laakso
Marku
M
Lumiaho
Anne
A
Lamnissou
Klea
K
Magistroni
Riccardo
R
Parfrey
Patrick
P
Breuning
Martijn
M
Peters
Dorien J M
DJ
Torra
Roser
R
Winearls
Christopher G
CG
Torres
Vicente E
VE
Harris
Peter C
PC
Paterson
Andrew D
AD
Pei
York
Y
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D018925:Chemokines; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050396:TRPP Cation Channels / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D050396:TRPP Cation Channels; C498624:DKK3 protein, human