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Homo sapiens

ABSTRACT: Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects [glomerulus]

OTHER RELATED OMICS DATASETS IN: GSE68127

PROVIDER: PRJNA282092 | ENA |

REPOSITORIES: ENA

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Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects

Project description:Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects

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Homo sapiens

Project description:Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects [tubulointerstitium]

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Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects [tubulointerstitium]

Project description:Tubulointersitial expression data from human kidney biopsy in African American subjects with glomerulopathies We used microarrays to analyze the transcriptome of African American subjects with glomerulopathies and the association of expression with APOL1 risk alleles (G1 and G2)

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Integrative genomics identifies novel associations with APOL1 risk genotype in African American NEPTUNE subjects [glomerulus]

Project description:Glomerular expression data from human kidney biopsy in African American subjects with glomerulopathies We used microarrays to analyze the transcriptome of African American subjects with glomerulopathies and the association of expression with APOL1 risk alleles (G1 and G2)

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APOL1 renal-risk variants induce mitochondrial dysfunction (Affymetrix 2)

Project description:To assess differential gene expression by APOL1 renal-risk (2 risk alleles) vs. non-risk (G0G0) genotypes in primary proximal tubule cells (PTCs), global gene expression (mRNA) levels were examined on Affymetrix HTA 2.0 arrays in primary PTCs cultured from non-diseased kidney in African Americans without CKD who underwent nephrectomy for localized renal cell carcinoma. To detect differentially expressed gene profiles attributable to APOL1 renal-risk genotypes, African American primary proximal tubule cells with two APOL1 renal-risk alleles (N=5) and lacking renal-risk alleles (N=25) were included in comparisons of global gene expression.

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Transcriptomic analysis of human podocytes [total RNA]

Project description:We analyzed the transcriptomic profiles of human podocyte-like epithelial cells (HUPEC) obtained from urine of two subjects with APOL1 low-risk (G0/G0) genotypes and two subjects with APOL1 high-risk (G1/G2) genotypes.

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Project description:We analyzed the small RNA profiles of human podocyte-like epithelial cells (HUPEC) obtained from urine of two subjects with APOL1 low-risk (G0/G0) genotypes and two subjects with APOL1 high-risk (G1/G2) genotypes.

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African American hepatocyte genotype

Project description:African American hepatocyte genotype

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Evaluation of APOL1 ASO in a novel model of APOL1-associated renal disease

Project description:African Americans develop end-stage renal disease at a higher rate compared to European Americans due to two polymorphisms (G1 and G2 risk variants) in the apolipoprotein L1 (APOL1) gene that are common in people of African ancestry. Not all homozygous risk allele carriers, however, develop renal disease suggesting that modifying factors (“second hits”) are required. Although the compelling genetic evidence provides an exciting opportunity for personalized medicine in chronic kidney disease (CKD), drug discovery efforts have been greatly hindered by the fact that APOL1 expression is limited to humans and select nonhuman primates. We describe a novel physiologically-relevant genomic mouse model of APOL1-associated renal disease that expresses human APOL1 from the endogenous human promoter, resulting in expression in similar tissues and at similar relative levels as humans. While naïve genomic APOL1 transgenic mice did not exhibit a renal disease phenotype, a single administration of IFNγ was sufficient to robustly induce proteinuria only in APOL1 G1 transgenic mice, despite inducing kidney APOL1 expression in both G0 and G1 mice, serving as a clinically-relevant “second hit.” We also report on the discovery of the first APOL1 inhibitor, IONIS-APOL1Rx, a Generation 2.5 antisense oligonucleotide (ASO) targeting APOL1 mRNA. Treatment of APOL1 G1 mice with IONIS-APOL1Rx prior to IFNγ challenge robustly and dose-dependently inhibited kidney and liver APOL1 expression and protected against IFNγ-induced proteinuria, indicating that the disease-relevant cell types are sensitive to ASO treatment. Collectively, these data suggest that IONIS-APOL1Rx may be an effective therapeutic for APOL1 nephropathies and warrants further development.

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Project description:African American-specific APOL1 risk variants in endothelial cells exacerbate sepsis and COVID19 severity

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