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/β-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.Autosomal dominant polycystic kidney disease ( ADPKD) is the most common monogenic kidney disease worldwide, affecting one in 500 to 1000 births.^1,2 It is characterized by focal development of renal cysts in an age-dependent manner. Typically, only a few renal cysts are clinically detectable during the first three decades of life; however, by the fifth decade, tens of thousands of renal cysts of different sizes can be found in most patients.³ Progressive cyst expansion with age leads to massive enlargement and distortion of the normal architecture of both kidneys and, ultimately, ESRD in most patients. ADPKD is also associated with an increased risk for cardiac valvular defects, colonic diverticulosis, hernias, and intracranial arterial aneurysms. Overall, ADPKD accounts for approximately 5% of ESRD in North America.²Mutations of PKD1 and PKD2 respectively account for approximately 85% and approximately 15% of linkage-characterized European families. Polycystin-1 (PC-1) and PC-2, the proteins encoded by PKD1 and PKD2, respectively, function as a macromolecular complex and regulate multiple signaling pathways to maintain the normal tubular structure and function.¹ Monoclonal expansion of individual epithelial cells that have undergone a somatic “second hit” mutation, resulting in biallelic inactivation of either PKD1 or PKD2, seems to provide a major mechanism for focal cyst initiation,⁴ possibly through the loss of polycystin-mediated mechanosensory function in the primary cilium.⁵ In addition, a large prospective, observational study indicated that renal cysts in ADPKD expand exponentially with increasing age, and patients with large polycystic kidneys are at higher risk for developing kidney failure⁶; however, the key factors that modulate renal disease progression in ADPKD remain incompletely understood.Renal disease severity in ADPKD is highly variable, with the age of onset of ESRD ranging from childhood to old age.^7–11 A strong genetic locus effect has been noted in ADPKD. Adjusted for age and gender, patients with PKD1 have larger kidneys and earlier onset at ESRD than patients with PKD2 (mean age at ESRD 53.4 versus 72.7 years, respectively).^8,9 By contrast, a weak allelic effect (based on the 5′ versus 3′ location of the germline mutations) on renal disease severity may be present for PKD1¹⁰ but not PKD2.¹¹ Marked intrafamilial variability in renal disease is well documented in ADPKD and suggests a strong modifier effect.^10–15 In an extreme example, large polycystic kidneys were present in utero in one of a pair of dizygotic twins affected with the same germline PKD1 mutation, whereas the kidneys of the co-twin remained normal at 5 years of age.¹² Several studies have quantified the role of genetic background in the phenotypic expression of ADPKD. In a comparison of monozygotic twins and siblings, greater variance in the age of onset of ESRD in the siblings supported a role for genetic modifiers.¹³ Two other studies of intrafamilial disease variability in PKD1 have estimated that genetic factors may account for 32 to 42% of the variance of creatinine clearance before ESRD and 43 to 78% of the variance in age at ESRD.^14,15 The magnitude of the modifier gene effect from these studies suggests that mapping such factors is feasible. Here, we report the results of an association study of modifier genes for PKD1 renal disease severity.