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Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression.

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.

SUBMITTER: Papeta N

PROVIDER: S-EPMC2673856 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression.

Papeta Natalia N Chan Ka-Tak KT Prakash Sindhuri S Martino Jeremiah J Kiryluk Krzysztof K Ballard David D Bruggeman Leslie A LA Frankel Rachelle R Zheng Zongyu Z Klotman Paul E PE Zhao Hongyu H D'Agati Vivette D VD Lifton Richard P RP Gharavi Ali G AG

The Journal of clinical investigation 20090420 5

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 hom ...[more]

PMID: 19381020

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Project description:ObjectiveTo compare the genetic architecture of susceptibility variants of IgA nephropathy (IgAN) in Chinese and Europeans.MethodsWe selected the independent genome-wide significant variants of IgAN in European population as candidate variants. Their associations, risk alleles, risk allele frequencies, odds ratios and population attributable risk scores were derived and calculated, then compared with those in the current Chinese population, including 1 194 IgAN patients and 902 controls. Using the significant variants, genetic risk scores were calculated and compared between the East Asians and the Europeans. The correlation between the genetic risk scores and clinical manifestations was also evaluated.ResultsThere were 16 independent single nucleotide polymorphisms (SNPs) located in 11 loci showing significantly association with susceptibility to IgAN in the Europeans. 93.75% (15/16) of them also showed significant associations in the Chinese (P<0.05). The effects of all the associated SNPs were in the same direction, either risk or being protective for IgAN, between the Chinese and the Europeans. On the contrary, remarkable higher risk allelic odds ratio (P=1.94×10-2), higher risk allele frequency (P=3.09×10-2), and higher population attributable risk (P=3.03×10-4) were observed for most of the associated SNPs in the Chinese than in the Europeans. Furthermore, genetic risk scores were significantly larger in the Asian populations compared with the Europeans (P=1.78×10-163). While there was no significance among the subpopulations in both the East Asians and the Europeans. Compared with the healthy controls, the genetic risk score in the IgAN patients was significantly larger (P=3.60×10-27). Clinical analysis showed the genetic risk score was positively associated with serum levels of IgA and IgA1, phases of chronic kidney disease and Haas grades.ConclusionOur study provides further evidence in the shared genetic architecture between Chinese and Europeans, while differences with respect to the effect sizes and risk allele frequencies across ethnicities, contributing partially to the differences of disease prevalence.

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Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression.

Publications

Susceptibility loci for murine HIV-associated nephropathy encode trans-regulators of podocyte gene expression.

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