Abstract: PO1333
Genome-Wide Association Study in Mice Maps Susceptibility to HIV-Associated Nephropathy to the Ssbp2 Locus
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Steers, Nicholas J., Columbia University Irving Medical Center, New York, New York, United States
- Gupta, Yask, Columbia University Irving Medical Center, New York, New York, United States
- D'Agati, Vivette D., Columbia University Irving Medical Center, New York, New York, United States
- Lim, Tze Yin, Columbia University Irving Medical Center, New York, New York, United States
- Mo, Anna, Columbia University Irving Medical Center, New York, New York, United States
- Liang, Judy, Columbia University Irving Medical Center, New York, New York, United States
- Stevens, Kelsey O., Columbia University Irving Medical Center, New York, New York, United States
- Demaria, Natalia D., Columbia University Irving Medical Center, New York, New York, United States
- Lam, Wan Yee, Columbia University Irving Medical Center, New York, New York, United States
- Nagarajan, Lalitha, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
- Sanna-Cherchi, Simone, Columbia University Irving Medical Center, New York, New York, United States
- Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States
Background
To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of focal segmental glomerulosclerosis that often arises in the setting of viral infections, we performed a genome wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN).
Methods
F1 hybrids were generated between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Histology, BUN, proteinuria and urinary NGAL were assessed in the F1 hybrids. A GWAS in 366 transgenic F1 hybrids generated from these 20 inbred strains was performed.
Results
Six stains (A/J, C3H/HeJ, DBA/1J, KK/HIJ , WSB/EiJ , and LP/J) were highly sensitive to the Tg resulting in severe glomerulosclerosis, 9 strains (129S1/SvImJ, Balb/CJ, C57BL/6J, C57BL/6NJ, C57BL/10J, C57BL/J, C58/J, CAST/EiJ and NZB/BINJ) were resistant to the Tg resulting in limited to no glomerulosclerosis, and 5 strains (CBA/J, DBA/2J, NOD/ShiLtJ, NZO/HlLtJ and FVB/NJ) had intermediate glomerulosclerosis. Analysis of histology, BUN and urinary NGAL demonstrated a marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS identified a genome-wide significant locus on Chr. 13 and multiple additional suggestive loci. Cross annotation of the Chr. 13 locus, including single cell transcriptomic analysis of wild type and HIV-1 transgenic mouse kidneys, nominated Ssbp2 as the likely culprit gene. Ssbp2 is highly expressed in podocytes, encodes a transcriptional cofactor present in LDB1 containing complexes, and interacts with LMX1B, a known FSGS gene that requires LDB1 for optimal transcriptional activity. Consistent with these data, older Ssbp2 null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis and inflammation, similar to the HIVAN mouse model.
Conclusion
These findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest Ssbp2 as susceptibility gene for HIVAN, potentially acting via the LDB1-LMX1B transcriptional network. Future studies will evaluate the role of Ssbp2 in vitro and in Ssbp2 null mice.
Funding
- Other U.S. Government Support