Abstract: SA-PO575
ADPKD Progression by Variant Type and Molecular Domain: An Evaluation of Time-Series Disease Trajectories among HALT Participants
Session Information
- Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Sucholeiki, Robert L., University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
- Jochum, Elena, University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
- Chapman, Arlene B., University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
- Chen, Peili, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States
- Wessely, Oliver, Cleveland Clinic, Cleveland, Ohio, United States
Group or Team Name
- University of Chicago Medicine Section of Nephrology.
Background
As the leading monogenic cause of kidney failure, autosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide. Understanding predictors of ADPKD severity is important for prognosis, long-term management, and treatment. Disease severity has been shown to depend on the gene affected by the pathogenic variant (PKD1 vs PKD2) and its truncating effect. However, the association between ADPKD disease phenotype and the location of genetic variants in functional polycystin protein domains is not understood.
Methods
We studied time-series height-adjusted total kidney volume (htTKV), eGFR, and Mayo Imaging Class (MIC) distribution among 334 early-stage patients with ADPKD in the HALT A dataset (a randomized clinical trial dataset of early-onset ADPKD individuals) to examine the impact of variant location in the PKD1 gene on disease progression over time. HALT A provided Sanger sequencing information for the pathogenic variant of each patient. We referenced the UniProt and cBioPortal genetic databases for protein domain information. We assigned non-truncating genetic variants (n=110) by location to key structural or functional domains in polycystin-1 or polycystin-2. We used RStudio to plot time-series htTKV and eGFR progressions and ran linear regressions for each participant. We compared patients’ longitudinal disease trajectories for truncating vs non-truncating variant status and the protein domain location of non-truncating PKD1 variants.
Results
PKD1 non-truncating pathogenic variants in the REJ (90.5 ml/m/year; 95% CI [66.5–112.5]) and PLAT (80.3 ml/m/year; 95% CI [58.0–102.6]) domains demonstrated rapid htTKV growth, while variants in the C-type lectin (26.8 ml/m/year; 95% CI [10.8–42.8]) and PKD repeat (19.6 ml/m/year; 95% CI [1.3–37.8]) domains demonstrated significantly slower growth (p<0.0001). Variants in these fast- and slow-progressing regions also showed clinically and statistically significant differences in MIC distribution (p<0.0001) and eGFR rate of change (-4.26 vs -2.67 ml/min/year; p<0.0001).
Conclusion
Our findings shed light on protein domain location as a clinically substantive marker of ADPKD disease progression that can be valuable for disease prognosis in early-stage patients with non-truncating variants in PKD1.