Modifier genes play a significant role in the phenotypic expression of PKD1

Polycystic kidney disease type 1 (PKD1) is characterized by extreme variation in the severity and progression of renal and extrarenal phenotypes. There are significant familial phenotype differences; but it is not clear if this is due to differences in PKD1 mutations, differences in genetic background, or both.

A total of 315 affected relatives (83 PKD1 families) without end-stage renal disease (ESRD) were evaluated for disease markers, including renal volume, creatinine clearance, proteinuria, liver cysts, and hypertension. Of these patients, 19% progressed to ESRD within 1 to 10 years after the initial examination. Nested analysis of variance was used to investigate interfamilial and intrafamilial differences in these phenotypes. Heritability analyses were used to estimate the effect of the genetic background on phenotypic variability. The age of onset of ESRD was also analyzed with an additional 389 family members from the same PKD1 families without clinical evaluation but with data on age of onset of ESRD (or age without ESRD).

There were significant phenotype differences between patients with the same mutation and different genetic backgrounds. The phenotypic variation between patients with different mutations and different genetic backgrounds was not significantly greater than the variation between patients with the same mutation and different genetic backgrounds. However, when the 389 family members were included, both the mutation and modifier genes had significant effects on the age of onset of ESRD. Inherited differences in genetic background were estimated to account for 18% to 59% of the phenotypic variability in PKD1 disease markers in patients prior to ESRD and in the subsequent progression to ESRD (43% heritability) in the 315 patients who were clinically evaluated.

Modifier loci in the genetic background are important factors in inter- and intrafamilial variability in the phenotypic expression of PKD1. The extreme intrafamilial phenotype differences are consistent with the hypothesis that one or a few modifier genes have a major effect on the progression and severity of PKD1.