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).

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.

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 Ssbp2 as the most likely candidate gene. Ssbp2 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 Ssbp2 null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model.

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.

为了深入了解塌陷性肾小球病（一种罕见的 FSGS，通常在病毒感染情况下出现）的发病机制，我们使用 HIV-1 相关肾病的小鼠模型在近交系小鼠品系中进行了全基因组关联研究 (GWAS) （艾滋病毒）。

我们首先在 FVB/NJ 背景下的 HIV-1 转基因小鼠和 20 个近交实验室品系之间产生了 F1 杂种。组织学、BUN 和尿 NGAL 分析表明转基因 F1 杂种之间存在显着的表型变异，为肾病易感性中的宿主遗传因素提供了强有力的证据。对这 20 个近交系产生的 365 个转基因 F1 杂种进行了 GWAS。

我们在 13-C3 号染色体上确定了一个全基因组重要位点和多个其他暗示性位点。 Chr 的交叉注释。 13 个基因座，包括野生型和 HIV-1 转基因小鼠肾脏的单细胞转录组分析，将Ssbp2提名为最有可能的候选基因。 Ssbp2在足细胞中高度表达，编码与 LDB1 和 LMX1B 相互作用的转录辅助因子，这两种因子先前都与 FSGS 有关。与这些数据一致的是，老年Ssbp2缺失小鼠自发出现肾小球硬化、肾小管管型、间质纤维化和炎症，类似于 HIVAN 小鼠模型。

这些发现证明了 GWAS 在小鼠中的实用性，可以揭示罕见肾脏特征的宿主遗传因素，并表明Ssbp2作为 HIVAN 的易感基因，可能通过LDB1-LMX1B 转录网络发挥作用。