Genetic Determinants of Focal Segmental Glomerulosclerosis in Mouse and Humans

Focal segmental glomerulosclerosis (FSGS) is a disease affecting the filtering unit of the kidney the glomerulus, which is characterized by a high morbidity, poor response to medical therapy, and a high rate of progression to end-stage renal disease (ESRD) requiring dialysis or transplant. Individuals of African ancestry have a four-fold increased risk of FSGS compared to Asians or Caucasians, suggesting a strong genetic contribution. Familial forms of disease account for a small proportion of cased with FSGS, and genetic variants in the gene called APOL1 do not fully explain the racial disparities in disease risk. These data suggest that other, yet unknown, common rare genetic factors and modifiers are also contributing to FSGS of individuals of both African and non-African descent.

Genetic studies for human FSGS have traditionally explored only one genetic model at a time, either rare variants responsible for rare or familial forms of disease, or common genetic variants, but with the exception of our initial study, there are no studies that have approached this disease in a comprehensive fashion using both human and mouse genetic studies, transcriptomics, and cellular systems.

In this proposal, our hypothesis, combining genetic studies across two different species and transcriptomic analysis of mice resistant and susceptible to FSGS, will augment analytical power to shed light on the genetic modifiers of APOL1 and the pathogenesis of FSGS. We will leverage a uniquely large cohort of patients with APOL1 variants, and our prior work for identifying susceptibility genes to FSGS, and state-of-the-art analytical tools to solve the genetic modifiers of APOL1-nephropathy and collapsing FSGS.

We will interrogate both common and rare genetic variants in humans and mice that will generate new datasets, which in combination with our previously generated datasets and publicly available resources, will allow the identification of novel genes, genetic variants, and genetic modifiers involved in the pathology of collapsing FSGS. This will be a comprehensive study using exome-wide association studies and transcriptomic analysis, bridging a deficit in the knowledge in studies for this frequent cause of kidney failure.

In the short term, this study is designed to provide insight into the genetic modifiers of collapsing FSGS and identifying genes causally related to disease. In the long term, we anticipate developing new models for collapsing FSGS in order to devise new targeted therapies that will impact the benefit and treatment for chronic kidney disease at large in the general population as well as in active-duty personnel, Veterans and their families.