APOL1 - associated nephropathy from human-derived, intrarenal perspective

Boston Children'S Hospital, Boston MA

Investigators

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Abstract

Nephrotic syndrome (NS) is a rare form of chronic kidney disease resulting from glomerular filtration barrier failure and massive proteinuria. To achieve increasingly effective care for NS, a more precise understanding of its underlying molecular mechanisms is necessary. Human genetics studies in NS using family- and population- based methods have proven effective in doing so. In the US, chronic and end stage kidney disease (CKD/ESKD) disproportionally affects African Americans. Social determinants certainly contribute to these health disparities. However, it is now clear that a major contributor to the large excess risk of kidney disease for Black people in the US is a genetic factor, namely common variants in apolipoprotein L1 (APOL1). One in eight Black Americans (13%) carry two APOL1 risk variants, which constitutes a high-risk (HR) genotype. The APOL1 HR genotype is associated with a 15-20x increased odds of focal segmental glomerulosclerosis (FSGS). The combination of the HR genotype's high frequency in the Black population and its outsized effect size for FSGS results means that African Americans with a HR genotype have a 5-10% lifetime risk of FSGS and that ~70% of all Black patients with FSGS have APOL1-mediated FSGS (AMFSGS). Based on our own work and that of our colleagues globally in the fields of both APOL1 kidney diseases specifically and Precision Medicine of diverse human diseases more broadly, our overarching conceptual model is that one day we will be able to treat, cure, or even prevent the majority of AMFSGS cases by using genomics and multiomics to gain a deep understanding of the molecular anatomy of this disease. To do this we must discover the full set of (1) genetic and environmental modifiers that increase the penetrance of FSGS among people (of any race or ethnicity) with a HR genotype, and (2) mechanistic pathways that, upon onset of AMFSGS, cause initial kidney cell injury and progressive glomerular injury, failure, and tubulointerstitial inflammation and fibrosis. In Aim 1, we will discover genetic modifiers of AMFSGS via genome-wide association studies (GWAS). In Aim 2, we will integrate GWAS data, multi-tissue bulk and single-cell omics datasets, and functional assays to functionally characterize the pathobiology of genetically-driven modifiers of AMFSGS. In Aim 3, we will discover the transcriptome-wide consequences of a HR genotype and APOL1's cis-regulation at cell-specific resolution using kidney snRNA-seq and snRNA-seq + ATAC-seq datasets and functional assays. This proposal will result in the discovery of multiple genetic modifiers of AMFSGS and specific genes, pathways, and cell types underlying its pathology. By discovering multiple molecular drivers of this condition, we will help pave the way for subsequent development of targeted therapies that can be used alone or in combination to treat, or even cure, people who already have AMFSGS. Beyond this, for healthy children and adults in our community with a HR genotype, discovering genetic factors that increase the penetrance of AMFSGS would allow efforts to be undertaken to devise pharmacologic or lifestyle strategies to prevent disease from ever occurring in community members at a greater risk of developing it.