title: A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis.
abstract: Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.forename: Mykyta
authors.initials: M
authors.lastname: Artomov
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brähler
authors.forename: M Christine
authors.initials: MC
authors.lastname: Stander
authors.forename: Ghaidan
authors.initials: G
authors.lastname: Shamsan
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Sampson
authors.forename: J Michael
authors.initials: JM
authors.lastname: White
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Robi D
authors.initials: RD
authors.lastname: Mitra
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide