biostudies-literatureSteers NJDepartment of Defense108-120https://www.ebi.ac.uk/biostudies/studies/S-EPMC8763192biostudies-literatureUnknown33(1)<h4>Background</h4>To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS 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).<h4>Methods</h4>We first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed.<h4>Results</h4>We identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated <i>Ssbp2</i> as the most likely candidate gene. <i>Ssbp2</i> is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older <i>Ssbp2</i> null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model.<h4>Conclusions</h4>These findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest <i>Ssbp2</i> as susceptibility gene for HIVAN, potentially acting <i>via</i> the LDB1-LMX1B transcriptional network.Journal of the American Society of Nephrology : JASNGWAS in Mice Maps Susceptibility to HIV-Associated Nephropathy to the <i>Ssbp2</i> Locus.PMC8763192W81XWH-16-1-0450GRANT12019690DeMaria NMo AStevens KOGupta YNagarajan LGagea MAhram DFSanna-Cherchi SLam WYD'Agati VDLiang JSteers NJGharavi AGLim TYfalseGWAS in Mice Maps Susceptibility to HIV-Associated Nephropathy to the <i>Ssbp2</i> Locus.<h4>Background</h4>To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS 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).<h4>Methods</h4>We first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed.<h4>Results</h4>We identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated <i>Ssbp2</i> as the most likely candidate gene. <i>Ssbp2</i> is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older <i>Ssbp2</i> null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model.<h4>Conclusions</h4>These findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest <i>Ssbp2</i> as susceptibility gene for HIVAN, potentially acting <i>via</i> the LDB1-LMX1B transcriptional network.2022-01-01T00:00:00Z2022 Jan2026-07-16T17:23:15.059Z2025-04-06T09:44:01.949ZS-EPMC87631923489353410.1681/asn.202104054310.1681/ASN.2021040543