A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

Haiyang Yu, Mykyta Artomov, Sebastian Brähler, M. Christine Stander, Ghaidan Shamsan, Matthew G. Sampson, J. Michael White, Matthias Kretzler, Jeffrey H. Miner, Sanjay Jain, Cheryl A. Winkler, Robi D. Mitra, Jeffrey B. Kopp, Mark J. Daly, Andrey S. Shaw

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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 FSGSsusceptible 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.

Original languageEnglish (US)
Pages (from-to)1067-1078
Number of pages12
JournalJournal of Clinical Investigation
Volume126
Issue number3
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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