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- Title
Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression.
- Authors
Papeta, Natalia; Chan, Ka-Tak; Prakash, Sindhuri; Martino, Jeremiah; Kiryluk, Krzysztof; Ballard, David; Bruggeman, Leslie A; Frankel, Rachelle; Zheng, Zongyu; Klotman, Paul E; Zhao, Hongyu; D'Agati, Vivette D; Lifton, Richard P; Gharavi, Ali G
- Abstract
Multiple studies have linked podocyte gene variants to diverse sporadic nephropathies, including HIV-1-associated nephropathy (HIVAN). We previously used linkage analysis to identify a major HIVAN susceptibility locus in mouse, HIVAN1. We performed expression quantitative trait locus (eQTL) analysis of podocyte genes in HIV-1 transgenic mice to gain further insight into genetic susceptibility to HIVAN. In 2 independent crosses, we found that transcript levels of the podocyte gene nephrosis 2 homolog (Nphs2), were heritable and controlled by an ancestral cis-eQTL that conferred a 3-fold variation in expression and produced reactive changes in other podocyte genes. In addition, Nphs2 expression was controlled by 2 trans-eQTLs that localized to the nephropathy susceptibility intervals HIVAN1 and HIVAN2. Transregulation of podocyte genes was observed in the absence of HIV-1 or glomerulosclerosis, indicating that nephropathy susceptibility alleles induce latent perturbations in the podocyte expression network. Presence of the HIV-1 transgene interfered with transregulation, demonstrating effects of gene-environment interactions on disease. These data demonstrate that transcript levels of Nphs2 and related podocyte-expressed genes are networked and suggest that the genetic lesions introduced by HIVAN susceptibility alleles perturb this regulatory pathway and transcriptional responses to HIV-1, increasing susceptibility to nephropathy.
- Publication
The Journal of clinical investigation, 2009, Vol 119, Issue 5, p1178
- ISSN
1558-8238
- Publication type
Journal Article
- DOI
10.1172/JCI37131