Genetic studies of HIV associated nephropathy

The goals of this project are to apply genetic approaches to identify molecular pathways underlying HIVAN. Using mapping cohorts between mice with contrasting susceptibility to HIVAN, we have previously identified four loci that predispose to nephropathy (HIVAN1-4). We have also confirmed findings by examination of congenic and consomic mice that captured the HIVAN1 and HIVAN2 intervals. Meiotic mapping and gene expression analysis in these lines have identified high likelihood positional candidates for HIVAN1 and HIVAN2 genes. We have further combined linkage analysis with gene expression profiling in F2 segregants to identify molecular pathways and primary mediators of nephropathy. This analysis has demonstrated that the HIVAN1-3 loci encode transregulators of podocyte gene expression (e.g. Nephrin, Podocin, Synaptopdin, MYH9) and belong to a molecular network that modulates podocyte architecture and expression of components of the glomerular filtration barrier. Moreover, application of a likelihood-based algorithm in our F2 cross strongly implicated non-muscle myosin heavy chain 9 (Myh9) as a pathogenic mediator of nephropathy. These data indicate that the HIVAN1-3 genes operate in a common pathway, suggesting that identification of the genes and associated molecular mediators will provide insight into the pathogenesis of human nephropathy.

We will identify the HIVAN1 and HIVAN2 genes, using a combination of meiotic and IBD mapping in congenic strains, gene expression analysis and functional studies in podocytes. Confirmation will be performed by transgenic rescue. We will apply a likelihood-based algorithm to linkage of gene expression data to identify causal mediators of HIVAN and a molecular network underlying disease. Finally, we will validate the molecular network in an independent HIVAN mapping cohort and determine whether variation in genes identified as causal mediators are associated with HIVAN and other forms of nephropathy in humans.