| Authors: | Papeta N, Chan KT, Prakash S, Martino J, Kiryluk K, Ballard D, Bruggeman LA, Frankel R, Zheng Z, Klotman PE, Zhao H, D\'Agati VD, Lifton RP, Gharavi AG |
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| Title: | Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression. |
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| Journal: | The Journal of clinical investigation
May 2009 , Vol 119 , pp. 1178-88 |
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| 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.
PUBMED: 19381020
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| Ontological Annotations: |
- D040641: Quantitative Trait Loci (Publication, NCBO Annotator)
- D051379: Mice (Publication, NCBO Annotator)
- MP:0005264: glomerulosclerosis (Publication, NCBO Annotator)
- GO:0010467: gene expression (Publication, NCBO Annotator)
- D015497: HIV-1 (Publication, NCBO Annotator)
- D008822: Mice, Transgenic (Publication, NCBO Annotator)
- D019076: Transgenes (Publication, NCBO Annotator)
- D020022: Genetic Predisposition to Disease (Publication, NCBO Annotator)
- D016263: AIDS-Associated Nephropathy (Publication, NCBO Annotator)
- D000483: Alleles (Publication, NCBO Annotator)
- D050199: Podocytes (Publication, NCBO Annotator)
- D009401: Nephrosis (Publication, NCBO Annotator)
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