Genetic variation of DKK3 may modify renal disease severity in ADPKD

Abstract

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.

Figure 1.

Detection and adjustment of population structure by multidimensional scaling (MDS). C1 separates patients along a northwest-southeast axis of their European ancestry. North Americans form an admixed group along this axis. C2 separates the Fins from the Newfoundlanders. Five outliers were subsequently identified to be black.

Figure 2.

Differential expression of DKK3 in human PKD1 renal cysts. (A) Differential expression of selected component and target genes suggesting aberrant activation of Wnt/β-catenin signaling pathway in renal cysts (n = 13) compared with minimally cystic tissues (MCT; n = 5) from human PKD1 kidneys (false-discovery rate <0.5%). The expression pattern of these genes in MCT and normal renal cortical tissue (Kidney; n = 3) is very similar. Upregulated genes are shown in red, and downregulated genes are shown in green. (B) Real-time RT-PCR analysis of DKK3 in an expanded sample set (Cyst = 38; MCT = 16; Kidney = 4). Data are means ± SEM; one-way ANOVA with Tukey multiple comparisons posttest. SC, small cysts; MC, medium cysts; LC, large cysts.