<i>UBD</i>
            modifies
            <i>APOL1</i>
            -induced kidney disease risk

Zhang, Jia Yue; Wang, Minxian; Tian, Lei; Genovese, Giulio; Yan, Paul; Wilson, James G.; Thadhani, Ravi; Mottl, Amy K.; Appel, Gerald B.; Bick, Alexander G.; Sampson, Matthew G.; Alper, Seth L.; Friedman, David J.; Pollak, Martin R.

doi:10.1073/pnas.1716113115

Cited by 58 publications

(50 citation statements)

References 35 publications

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“…Additional genetic and environmental contributors could provide a mechanism to explain both the incomplete penetrance of CKD in high-risk genotype subjects and also the clinical and pathological differences in the APOL1-associated CKDs. Preliminary studies have identified polymorphisms in NPHS2, BMP4, SDCCAG4, and UBD that modify APOL1-mediated CDK risk (7,25,64). However, a recent meta-analysis of genome-wide association data concluded there are likely few genetic factors that contribute a strong modifying second hit to APOL1-associated CKD risk and concludes the critical second-hit stressors for disease induction are more likely to be environmental (29).…”

Section: Gene-environment Interaction and Second-hit Stressorsmentioning

confidence: 99%

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Bruggeman

O’Toole

Sedor

2019

American Journal of Physiology-Renal Physiology

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The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

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Section: Gene-environment Interaction and Second-hit Stressorsmentioning

confidence: 99%

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Bruggeman

O’Toole

Sedor

2019

American Journal of Physiology-Renal Physiology

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“…[17][18][19] In an NS GLOM eQTL study of apolipoprotein L1 (APOL1), ubiquitin D (UBD) was significantly upregulated in individuals with a high-risk (HR) APOL1 genotype. 20 These findings were subsequently followed up in an admixture mapping study that identified enriched African ancestry at the UBD locus in people with a HR genotype and FSGS versus no FSGS and protective effects of UBD expression on the viability of cells overexpressing APOL1 risk variants, 21 providing additional support for UBD's involvement in APOL1-attributed NS.…”

Section: Introductionmentioning

confidence: 98%

An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome

Gillies¹,

Putler²,

Menon³

et al. 2018

The American Journal of Human Genetics

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158

145

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Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map these signals, eQTLBMA to discover GLOM- or TI-specific eQTLs, and single-cell RNA-seq data of control kidney tissue to identify the cell type specificity of significant eQTLs. We integrated eQTL data with an IgA Nephropathy (IgAN) GWAS to perform a transcriptome-wide association study (TWAS). We discovered 894 GLOM eQTLs and 1,767 TI eQTLs at FDR < 0.05. 14% and 19% of GLOM and TI eQTLs, respectively, had >1 independent signal associated with its expression. 12% and 26% of eQTLs were GLOM specific and TI specific, respectively. GLOM eQTLs were most significantly enriched in podocyte transcripts and TI eQTLs in proximal tubules. The IgAN TWAS identified significant GLOM and TI genes, primarily at the HLA region. In this study, we discovered GLOM and TI eQTLs, identified those that were tissue specific, deconvoluted them into cell-specific signals, and used them to characterize known GWAS alleles. These data are available for browsing and download via our eQTL browser, "nephQTL."

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“…We first plotted genes previously identified by other studies to be potential modifiers of APOL1-mediated kidney disease. A large linkage disequilibrium block on chromosome 6 containing UBD and PPP1R18 may house disease-modulating genes 26,27 , with visible differences between APOL1 genotypes in UBD and PPP1R18 expression in the tubule and endothelial clusters ( Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

ProfilingAPOL1Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics

Liu

Radmanesh

Chung

et al. 2019

Preprint

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Running Title: APOL1 Variant Organoid scRNA-seq Word Count: 205 (Abstract), 1736 (Main Text, excluding Methods)ABSTRACT Background DNA variants in APOL1 associate with kidney disease, but the pathophysiological mechanisms remain incompletely understood. Model organisms lack the APOL1 gene, limiting the degree to which disease states can be recapitulated. Here we present single-cell RNA sequencing (scRNAseq) of genome-edited human kidney organoids as a platform for profiling effects of APOL1 risk variants in diverse nephron cell types. MethodsWe performed footprint-free CRISPR-Cas9 genome editing of human induced pluripotent stem cells (iPSCs) to knock in APOL1 high-risk G1 variants at the native genomic locus. iPSCs were differentiated into kidney organoids, treated with vehicle, IFN-g, or the combination of IFN-g and tunicamycin, and analyzed with scRNA-seq to profile cell-specific changes in differential gene expression patterns, compared to isogenic G0 controls. ResultsBoth G0 and G1 iPSCs differentiated into kidney organoids containing nephron-like structures with glomerular epithelial cells, proximal tubules, distal tubules, and endothelial cells.Organoids expressed detectable APOL1 only after exposure to IFN-g. scRNA-seq revealed cell type-specific differences in G1 organoid response to APOL1 induction. Additional stress of tunicamycin exposure led to increased glomerular epithelial cell dedifferentiation in G1 organoids. ConclusionsSingle-cell transcriptomic profiling of human genome-edited kidney organoids expressing APOL1 risk variants provides a novel platform for studying the pathophysiology of APOL1mediated kidney disease.

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UBD modifies APOL1 -induced kidney disease risk

Cited by 58 publications

References 35 publications

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

An eQTL Landscape of Kidney Tissue in Human Nephrotic Syndrome

ProfilingAPOL1Nephropathy Risk Variants in Genome-Edited Kidney Organoids with Single-Cell Transcriptomics

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