Identifying genetic modifiers of autosomal recessive polycystic kidney disease (1179.1)

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) affects 1/20000 live births and is ~35% neonatal lethal, with ~50% of the surviving patients developing end‐stage renal disease (ESRD) within the first decade of life. ARPKD is caused by mutations in the PKHD1 gene in both humans and the orthologous rat model of ARPKD, the PCK rat. Identifying genetic modifiers of ARPKD in humans is challenging due to genetic heterogeneity and environmental variability. To circumvent this, we and others have turned to rodent models of ARPKD for candidate gene discovery. We identified 2 genetic backgrounds (FHH and SS) that attenuate ARPKD severity compared with the SD background of the original PCK rat. Compared with renal cyst formation in the SD.PCK rat (26±4), FHH.PCK (5±2; P<0.001) and SS.PCK (8±2; P<0.001) had significantly reduced cysts per renal cross‐section at 30 days of age. Reduced cyst formation was also confirmed by significantly decreased FHH.PCK (1.4±0.1g; P<0.001) and SS.PCK (1.7±0.1g; P<0.001) kidney weights compared with SD.PCK (3.1±0.2g) at 30 days of age. We hypothesized that genetic modifiers of ARPKD severity are likely shared by SS and FHH backgrounds. To identify these modifiers, renal transcripts were analyzed by microarray, which revealed 18 transcripts that concordantly changed in expression in FHH.PCK and SS.PCK kidneys (30 day), but not SD.PCK. Sequence analysis of the FHH.PCK, SS.PCK, and SD.PCK genomes showed that 5 out of 18 transcripts (Ndrg1, Hsd3b, Fmo1, Grtp1, and Proc1) reside in regions that are significantly enriched with variants that are shared by FHH.PCK and SS.PCK but not SD.PCK, suggesting the presence of common genetic modifiers of ARPKD. Collectively, these data provide 5 novel candidate modifiers of ARPKD risk for mechanistic follow‐up.